WO2012116257A1 - Anti-viral compounds - Google Patents

Anti-viral compounds Download PDF

Info

Publication number
WO2012116257A1
WO2012116257A1 PCT/US2012/026456 US2012026456W WO2012116257A1 WO 2012116257 A1 WO2012116257 A1 WO 2012116257A1 US 2012026456 W US2012026456 W US 2012026456W WO 2012116257 A1 WO2012116257 A1 WO 2012116257A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
independently
membered
alkyl
halogen
Prior art date
Application number
PCT/US2012/026456
Other languages
English (en)
French (fr)
Inventor
David A. Degoey
Warren M. Kati
Charles W. Hutchins
Pamela L. Donner
Allan C. Krueger
John T. Randolph
Sachin V. Patel
Mark A. Matulenko
Ryan G. Keddy
Tammie K. Jinkerson
Danchun LIU
John K. Pratt
Todd W. Rockway
Clarence J. Maring
Douglas H. HUTCHINSON
Charles A. Flentge
Rolf Wagner
David A. Betebenner
Kathy Sarris
Kevin R. Woller
William A. Carroll
Yi Gao
Original Assignee
Abbvie Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abbvie Inc. filed Critical Abbvie Inc.
Priority to ES12716757.5T priority Critical patent/ES2624246T3/es
Priority to MX2013009763A priority patent/MX346264B/es
Priority to CN201280020257.2A priority patent/CN103596941B/zh
Priority to CA2828495A priority patent/CA2828495A1/en
Priority to JP2013555589A priority patent/JP2014510063A/ja
Priority to EP12716757.5A priority patent/EP2678334B1/en
Publication of WO2012116257A1 publication Critical patent/WO2012116257A1/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D453/00Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/06Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing isoquinuclidine ring systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10Spiro-condensed systems
    • C07D491/113Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the present invention relates to compounds effective in inhibiting replication of Hepatitis C virus ("HCV").
  • HCV Hepatitis C virus
  • the present invention also relates to compositions comprising these compounds and methods of using these compounds to treat HCV infection.
  • HCV is an RNA virus belonging to the Hepacivirus genus in the Flaviviridae family.
  • the enveloped HCV virion contains a positive stranded RNA genome encoding all known virus-specific proteins in a single, uninterrupted, open reading frame.
  • the open reading frame comprises approximately 9500 nucleotides and encodes a single large polyprotein of about 3000 amino acids.
  • the polyprotein comprises a core protein, envelope proteins El and E2, a membrane bound protein p7, and the non-structural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B.
  • HCV infection is associated with progressive liver pathology, including cirrhosis and hepatocellular carcinoma.
  • Chronic hepatitis C may be treated with peginterferon-alpha in combination with ribavirin.
  • Substantial limitations to efficacy and tolerability remain as many users suffer from side effects, and viral elimination from the body is often inadequate. Therefore, there is a need for new drugs to treat HCV infection.
  • the present invention features compounds of Examples 3.46, 3.47, 3.48, 3.49,
  • compositions comprising these compounds or salts.
  • the compositions can also include additional therapeutic agents, such as HCV helicase inhibitors, HCV polymerase inhibitors, HCV protease inhibitors, HCV NS5A inhibitors, CD81 inhibitors, cyclophilin inhibitors, or internal ribosome entry site (IRES) inhibitors.
  • additional therapeutic agents such as HCV helicase inhibitors, HCV polymerase inhibitors, HCV protease inhibitors, HCV NS5A inhibitors, CD81 inhibitors, cyclophilin inhibitors, or internal ribosome entry site (IRES) inhibitors.
  • the present invention further features methods of using the compounds or salts of the present invention to inhibit HCV replication.
  • the methods comprise contacting cells infected with HCV virus with a compound or salt of the present invention, thereby inhibiting the replication of HCV virus in the cells.
  • the present invention features methods of using the compounds or salts of the present invention, or compositions comprising the same, to treat HCV infection.
  • the methods comprise administering a compound or salt of the present invention, or a pharmaceutical composition comprising the same, to a patient in need thereof, thereby reducing the blood or tissue level of HCV virus in the patient.
  • the present invention also features use of the compounds or salts of the present invention for the manufacture of medicaments for the treatment of HCV infection.
  • the present invention features processes of making the compounds or salts of the invention.
  • the present invention features compounds having Formula I, and pharmaceutically acceptable salts thereof,
  • X is C 3 -Ci 2 carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with one or more R A or R F ;
  • Li and L 2 are each independently selected from bond; or Ci-Cealkylene, C 2 -C 6 alkenylene or C2-C 6 alkynylene, each of which is independently optionally substituted at each occurrence with one or more R L ;
  • L 3 is bond or -L s -K-L s '-, wherein K is selected from bond, -0-, -S-, -N(R B )-, -C(O)-, -
  • a and B are each independently C3-Ci2carbocycle or 3- to 12-membered heterocycle, and are each independently optionally substituted with one or more
  • D is C 3 -Ci 2 carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with one or more RA; or D is C3-Ci2carbocycle or 3- to 12-membered heterocycle which is substituted with J and optionally substituted with one or more R A , where J is C 3 -
  • Ci2carbocycle or 3- to 12-membered heterocycle is optionally substituted with one or more R A , or J is -SF 5 ; or D is hydrogen or R A ;
  • Y is selected from -T'-C(RiR 2 )N(R 5 )-T-R D , -T'-C(R3R4)C(R 6 R 7 )-T-RD, -L K -T-R d , or - Ri and R2 are each independently R c , and R 5 is R B ; or Ri is Rc, and R2 and R 5 , taken together with the atoms to which they are attached, form a 3- to 12-membered heterocycle which is optionally substituted with one or more R A ;
  • R 3 , R4, R 6 , and R 7 are each independently R c ; or R 3 and R 6 are each independently R c , and R4 and R7, taken together with the atoms to which they are attached, form a 3- to 12- membered carbocycle or heterocycle which is optionally substituted with one or more R A ;
  • Z is selected from -T'-C(R 8 R9)N(R 12 )-T-R D , -T'-C(R 10 Rn)C(Ri3Ri4)-T-R D , L K — T— R D or
  • R 8 and R 9 are each independently R c , and R12 is R B ; or R 8 is R c , and R 9 and R12, taken together with the atoms to which they are attached, form a 3- to 12-membered heterocycle which is optionally substituted with one or more R A ;
  • Rio, Rn, Ri3, and R M are each independently Rc; or Ri 0 and R13 are each independently R c , and Rn and R14, taken together with the atoms to which they are attached, form a 3- to 12-membered carbocycle or heterocycle which is optionally substituted with one or more RA;
  • T and T are each independently selected at each occurrence from bond, -L s - -L s -M-L s '-, or -Ls-M-Ls'-M'-Ls"-, wherein M and M' are each independently selected at each occurrence from bond, -0-, -S-, N(R B )— , -C(O)-, -S(0) 2 - -S(O)-, -OS(O)-, - OS(0) 2 - -S(0) 2 0- -S(0)0-, -C(0)0- -OC(O)-, -OC(0)0-, -C(0)N(R B )-, - N(R B )C(0)-, -N(R B )C(0)0-, -OC(0)N(R B )-, -N(R B )S(0)-, -N(R B )S(0) 2 - - S(0)N(R B )-, -S(0) 2 N(
  • L K is independently selected at each occurrence from bond, -L s -N(R B )C(0)-L s '- or -L s - C(0)N(R B )-L s '-; or Ci-Cealkylene, C2-Cealkenylene or C2-Cealkynylene, each of which is independently optionally substituted at each occurrence with one or more R L ; or C 3 - Cncarbocycle or 3- to 12-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more RA;
  • E is independently selected at each occurrence from C3-Ci2carbocycle or 3- to 12-membered heterocycle, and is independently optionally substituted at each occurrence with one or more R A ;
  • R D is each independently selected at each occurrence from hydrogen or R A;
  • R A is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L S -RE, wherein two adjacent R A , taken together with the atoms to which they are attached and any atoms between the atoms to which they are attached, can optionally form carbocycle or heterocycle;
  • R B and R B ' are each independently selected at each occurrence from hydrogen; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to 6- membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in R B or R B ' is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 al
  • R c is independently selected at each occurrence from hydrogen, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or Q- Cealkyl, C2-Cealkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in Rc is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
  • R E is independently selected at each occurrence from -0-R s , -S-R s , -C(0)R s , -OC(0)R s , - C(0)OR s , -N(RsRs'), -S(0)R s , -S0 2 R s , -C(0)N(R s R s '), -N(R s )C(0)R s ', - N(Rs)C(0)N(R s 'Rs"), -N(R s )S0 2 R s ', -S0 2 N(R s R s '), -N(R s )S0 2 N(R s 'R s "), - N(Rs)S(0)N(R s 'Rs"), -OS(0)-R s , -OS(0) 2 -R s , -S(0) 2 OR s , -S(0)OR s ,
  • R F is independently selected at each occurrence from Ci-Ci 0 alkyl, C 2 -Ci 0 alkenyl or C 2 -
  • Cioalkynyl each of which contains 0, 1, 2, 3, 4 or 5 heteroatoms selected from O, S or N and is independently optionally substituted with one or more R L ; or -(R X -RY)Q-(R X -RY'), wherein Q is 0, 1, 2, 3 or 4, and each R x is independently O, S or N(R B ), wherein each R Y is independently Ci-Cealkylene, C 2 -Cealkenylene or C 2 -Cealkynylene each of which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano, and wherein each R Y ' is independently Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 - Cealkynyl each of which is independently optionally substituted with one or more substituents selected
  • R L is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, -0-R s , -S-R s , -C(0)R s , -OC(0)R s , -C(0)OR s , -N(R S R S '), - S(0)R s , -S0 2 R s , -C(0)N(R s R s ') or -N(R s )C(0)R s ' ; or C 3 -C 6 carbocycle or 3- to 6- membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C
  • L s , L s ' and L s " are each independently selected at each occurrence from bond; or Ci- C 6 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene, each of which is independently optionally substituted at each occurrence with one or more R L ; and
  • R s , Rs' and R s " are each independently selected at each occurrence from hydrogen; Q- Cealkyl, C 2 -Cealkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, -0-Ci-C 6 alkyl, -0-Ci-C 6 alkylene-0-Ci-C 6 alkyl, or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in R s , R s ' or R s ' is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy,
  • a and B preferably are independently selected from C 5 -C 6 carbocycle (e.g., phenyl), 5- to 6- membered heterocycle (e.g., pyridinyl or thiazolyl), or 8- to 12-membered bicycles such as where Zi is independently selected at each occurrence from O, S, NH or CH 2 , Z 2 is independently selected at each occurrence from N or CH, Z3 is independently selected at each occurrence from N or CH, Z4 is independently selected at each occurrence from O, S, NH or CH 2 , and Wi, W 2 , W 3 , W 4 , W 5 and W 6 are each independently selected at each occurrence from CH or N.
  • a and B are each independently optionally substituted with one or more R A .
  • A is selected from C 5 -C 6 carbocycle, 5- to 6-membered heterocycle, and is optionally substituted with one or more RA;
  • B is selected from C 5 -C 6 carbocycle, 5- to 6-membered heterocycle, or and is optionally substituted with one or more R A ; where Z Z 2 , Z 3 , Z 4 , Wi, W 2 ,
  • W 3 , W 4 , W 5 , W 6 are as defined above.
  • Z 3 is N and Z 4 is NH.
  • A can be selected from
  • both A and B are phenyl (e.g., both A and B ar Also highly preferably, A
  • A is and A and B are substituted with one or more halogen, such as F or CI. It was surprisingly discovered that when A and/or B were
  • halo-substituted benzimidazole e.g., A is and B is
  • the compounds of Formula I unexpectedly showed significantly improved pharmacokinetic properties, as compared to the same compounds but with unsubstituted benzimidazole.
  • the improvements in pharmacokinetics can be observed, for instance, as a greater total plasma level exposure, measured as the area under the curve (AUC) over a 24 hour period following oral dosing in mouse.
  • HCV genotype la mutant infection e.g., L31M, Y93H, or Y93N la mutant infection.
  • methods of using such compounds to treat HCV genotype la mutant infection comprise administering such a compound to a patient having HCV genotype la mutant (e.g., L31M, Y93H, or Y93N la mutant).
  • D preferably is selected from C 5 -C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12- membered bicycles, and is optionally substituted with one or more R A .
  • D can also be preferably selected from Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, and is optionally substituted with one or more substituents selected from R L .
  • D is C 5 -C 6 carbocycle (e.g., phenyl), 5- to 6- membered heterocycle (e.g., pyridinyl, pyrimidinyl, thiazolyl), or 6- to 12-membered bicycles (e.g., indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, benzo[d][l,3]dioxol-5-yl), and is substituted with one or more R M , where R M is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L S -R E .
  • D is phenyl, and is optionally substituted with one or more R A . More preferably, D is phe substituted with one or more R M , wherein R M is as defined
  • D is wherein R M is as defined above, and each
  • R N is independently selected from R D and preferably is hydrogen.
  • One or more R N can also preferably be halo such as F.
  • D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or more R A . More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or
  • D is , wherein R M is as defined above, and each R N is independently selected from R D and preferably is hydrogen.
  • R N can also preferably be halo such as F.
  • D is also preferably indanyl, 4,5,6,7- tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl, and is optionally substituted with one or more R A .
  • D is indanyl, 4,5,6, 7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more R M .
  • D is indanyl, 4,5,6, 7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more R M .
  • D is indanyl, 4,5,6, 7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more R M .
  • R M is substituted with one or more R M .
  • R M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-Cecarbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-
  • R M is halogen, hydroxy, mercapto, amino, carboxy; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 - Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.
  • R M is Ci-C 6 alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.
  • R M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or R M is -L S -R E , wherein L s is a bond or Ci-C 6 alkylene, and R E is - N(R S R S '), -O-Rs, -C(0)R s , -C(0)OR s , -C(0)N(R s R s '), -N(R s )C(0)R s ', -N(R s )C(0)OR s ', - N(R s )S0 2 R s ', -S0 2 R s , -SRs, or -P(0)(OR s ) 2 , wherein R s and R s ' can be, for example, each independently selected at each occurrence from (1) hydrogen or (2) Ci-Ceal
  • R M is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or Ci-C 6 alkyl (e.g., methyl, isopropyl, tert-butyl), C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy.
  • halogen e.g., fluoro, chloro, bromo, iodo
  • hydroxy, mercapto, amino, carboxy or Ci-C 6 alkyl (e.g., methyl, isopropyl, tert-butyl), C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituent
  • R M is CF 3 , - C(CF 3 ) 2 -OH, -C(CH 3 ) 2 -CN, -C(CH 3 ) 2 -CH 2 OH, or -C(CH 3 ) 2 -CH 2 NH 2 .
  • R M is -L s - R E where L s is a bond and R E is -N(R S R S ), -0-R s , -N(R s )C(0)OR s ', -N(R s )S0 2 R s ', -S0 2 R s , or - SR S .
  • R E is -N(Ci-C 6 alkyl) 2 (e.g., -NMe 2 ); -N(Ci-C 6 alkylene-0-Ci- C 6 alkyl) 2 (e.g. -N(CH 2 CH 2 OMe) 2 ); -N(Ci-C 6 alkyl)(Ci-C 6 alkylene-0-Ci-C 6 alkyl) (e.g.
  • R M is -L S -R E where L s is Ci-C 6 alkylene (e.g., -CH 2 - -C(CH 3 ) 2 -, -C(CH 3 ) 2 -CH 2 -) and R E is -0-R s , -C(0)OR s , - N(R s )C(0)ORs', or -P(0)(OR s ) 2 .
  • L s is Ci-C 6 alkylene (e.g., -CH 2 - -C(CH 3 ) 2 -, -C(CH 3 ) 2 -CH 2 -) and R E is -0-R s , -C(0)OR s , - N(R s )C(0)ORs', or -P(0)(OR s ) 2 .
  • R M is -Ci-C 6 alkylene-0-R s (e.g., -C(CH 3 ) 2 -CH 2 - OMe); -Ci-C 6 alkylene-C(0)OR s (e.g., -C(CH 3 ) 2 -C(0)OMe); -Ci-C 6 alkylene-N(R s )C(0)OR s ' (e.g., -C(CH 3 ) 2 -CH 2 -NHC(0)OCH 3 ); or -C 1 -C 6 alkylene-P(0)(OR s ) 2 (e.g., -CH 2 -P(0)(OEt) 2 ).
  • R M is -Ci-C 6 alkylene-0-R s (e.g., -C(CH 3 ) 2 -CH 2 - OMe); -Ci-C 6 alkylene-C(0)OR s (e.g., -C(CH 3 ) 2
  • R M is C 3 -C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, - C(0)OR s , or -N(R S R S ').
  • R M is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l- methylcycloprop-l-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1 - dioxidothiomorpholin-4-yl, 4-methylpiperazin-l-yl, 4-methoxycarbonylpiperazin-l -yl, pyrrolidin-1- yl, piperidin-l -yl, 4-methylpiperidin-l-yl, 3,5-dimethylpiperidin-l -yl, 4,4-difluoropiperidin-l-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl).
  • cycloalkyl e.g., cyclopropyl, 2,2-dichloro-
  • R M is Ci-C 6 alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF 3 ).
  • D is C 5 -C 6 carbocycle, 5- to 6-membered heterocycle or 6- to 12-membered bicycle and is substituted with J and optionally substituted with one or more R A
  • J is C 3 - Cecarbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R A .
  • J is substituted with a C 3 -C 6 carbocycle or 3- to 6- membered heterocycle, wherein said C 3 -C 6 carbocycle or 3- to 6-membered heterocycle is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or - N(R S R S '), and J can also be optionally substituted with one or more R A .
  • substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
  • D is C 5 - C 6 carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R A
  • J is C 3 -C 6 carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R A
  • J is at least substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 - C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or -N(
  • D is C 5 -C 6 carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R A
  • J is 6- to 12-membered bicycle (e.g., a 7- to 12-membered fused, bridged or spiro bicycle comprising a nitrogen ring atom through which J is covalently attached to D) and is optionally substituted with one or more R A .
  • D is phenyl and is substituted with J and optionally substituted with one or more R A
  • J is C 3 -C 6 carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R A
  • J is at least substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 ha C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or -
  • D is , wherein each R N is independently selected from R D and preferably is hydrogen or halogen, and J is C 3 -C 6 carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR S or -
  • D is , wherein each R N is independently selected from R D and preferably is hydrogen or halogen, and J is C 3 -C 6 carbocycle or 3- to 6-membered heterocycle and is substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or -
  • N(R S R S '), and J can also be optionally substituted with one or more R A .
  • D is and J is C 3 -C 6 carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R A
  • J is at least substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or -N(R s R s ').
  • D contains a halo-substituted carbocycle or heterocycle (e.g., a halo-substituted 5-6 membered carbocycle or heterocycle directly linked to X)
  • the compound of Formula I (as well as compounds of Formula I A , 3 ⁇ 4, Ic, ID, IE, IF or I G described below, and compounds of each embodiment described thereunder) can exhibit significantly improved inhibitory activity against HCV genotypes 2a, 2b, 3a or 4a and/or improved pharmacokinetic properties. Therefore, the present invention contemplates methods of using such compounds to treat HCV genotype 2a, 2b, 3a or 4a infection.
  • These methods comprise administering such a compound to a patient having HCV genotype 2a, 2b, 3a or 4a.
  • the present invention also contemplates the use of such compounds for the manufacture of a medicament for the treatment of HCV genotypes 2a, 2b, 3a
  • Suitable D for this purpose can be, for instance, as described above, wherein at least one R N is halo such as fluorine. Specific examples of suitable D
  • X preferably is C 5 -C 6 carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered bicycles, and is optionally substituted with one or more R A or R F .
  • X can also be C 5 -C 6 carbocycle or 5- to 6-membered heterocycle which is optionally substituted with one or more R A or R F , wherein two adjacent R A on X, taken together with the ring atoms to which they are attached, optionally form a 5-
  • X is , wherein X3 is
  • X4 is C2-C 4 alkylene, C 2 -C 4 alkenylene or C 2 - C 4 alkynylene, each of which optionally contains one or two heteroatoms selected from O, S or N; and X is optionally substituted with one or more R A or R F , and two adjacent R A on X, taken together with the ring atoms to which they are attached, can optionally form a 5- to 6-membered carbocycle or heterocycle.
  • X can be or , wherein X 3 is C and is directly linked to -L3-D, X4 is C2-C4alkylene, C2-C4alkenylene or C2-C4alkynylene each of which optionally contains one or two heteroatoms selected from O, S or N, and X is optionally substituted with one or more RA or R F , and two adjacent R A on X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle. Moreover, X can be or , wherein X 3 is C and is directly linked to -L3-D, X4 is C2-C4alkylene, C2-C4alkenylene or C2-C4alkynylene each of which optionally contains one or two heteroatoms selected from O, S or N, and X is optionally substituted with one or more RA or R F , and two adjacent R A on X, taken together with the ring atoms to
  • X4 is C2-C4alkylene, C2-C4alkenylene or C2- C4alkynylene each of which optionally contains one or two heteroatoms selected from O, S or N, and X is optionally substituted with one or more RA or R F , and two adjacent R A on X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle.
  • is independently selected at each occurrence from CH 2 , O, S or NH
  • X 2 is independently selected at each occurrence from CH or N
  • X 3 is N and is directly linked to -L 3 -D
  • X 3 ' is C and is directly linked to -L3-D
  • X is optionally substituted with one or more RA or R F , and two adjacent R A on X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered
  • X 2 is independently selected at each occurrence from CH or N
  • X 3 is N and is directly linked to -L 3 -D
  • X3 ' is C and is directly linked to -L 3 -D
  • X is optionally substituted with one or more R A or R F , and two adjacent R A on X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle.
  • X is or wherein X 3 is C(H) or N and is directly linked to -L 3 -D, X 3 ' is C and is directly linked to -L 3 -D, and wherein X is optionally substituted with one or more R A or R F , and two adjacent R A on X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle. More preferably, X 3 is N.
  • Non-limiting examples of X include:
  • Each X can be optionally substituted with one or more RA or R F , and two adjacent RA on X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle.
  • Non-limiting examples of preferred X include the following pyrrolidine rings, each of which is optionally substituted with one or more R A or R F :
  • the relative stereochemistry at the 2- and 5-positions of the above pyrrolidine ring may be either cis or trans.
  • the stereochemistries of optional substituents RA at the 3- or 4-positions of the pyrrolidine may vary relative to any substituent at any other position on the pyrrolidine ring.
  • the stereochemistry at any carbon may be either (R) or (S).
  • Non-limiting examples of preferred X also include the following pyrrole, triazole or thiomor holine rin s, each of which is optionally substituted with one or more R A or R F :
  • the relative stereochemistry at the 3- and 5-positions of the thiomorpholine ring may be either cis or trans.
  • X is wherein X 3 is N and is directly linked to -L 3 -D, and X is optionally substituted with one or more R A or R F .
  • R F is Ci-Cioalkyl, C2-Cioalkenyl or C2-Cioalkynyl, each of which contains 0, 1 , 2, 3, 4 or 5 heteroatoms selected from O, S or N and is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.
  • R F is Ci-Ci 0 alkyl, C 2 -Ci 0 alkenyl or C 2 -Ci 0 alkynyl, each of which contains 0, 1 , 2, 3, 4 or 5 O and is independently optionally substituted with one or more R L .
  • R F is -(R X -RY)Q-(R X -RY'), wherein Q is 0, 1 , 2, 3 or 4; each R x is independently O, S or N(R B ); each R Y is independently Ci-C 6 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene each of which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; and each R Y ' is independently Ci-Cealkyl, C2-C 6 alkenyl or C2-C 6 alkynyl each of which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or
  • each R x is O. More preferably, X is optionally substituted with one or more R A or R F , each R F is independently selected from Ci-Cioalkyl, C2-Cioalkenyl or C2-Cioalkynyl, each of which contains 0, 1 , 2 or 3 O and is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.
  • X is optionally substituted with one or more R A or R F , each R F is independently selected from -(0-Ci-C 6 alkylene)Q-(0-Ci-C 6 alkyl), wherein Q preferably is 0, 1 , 2 or 3.
  • Li and L 2 are preferably independently bond or Ci-C 6 alkylene
  • L 3 is preferably selected from bond, Ci-C 6 alkylene or -C(O)-
  • L u L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • L u L 2 and L 3 are each independently bond or Ci-C 6 alkylene (e.g., - CH 2 - or -CH 2 CH 2 -), and are each independently optionally substituted with one or more R L .
  • L L 2 and L 3 are bond.
  • Y is preferably selected from -L S -C(RiR 2 )N(R 5 )-T-R D; -L S -C(R 3 R4)C(R 6 R 7 )-T-RD, -G- C(RiR 2 )N(R 5 )-T-R D , -G-C(R 3 R4)C(R6R 7 )-T-RD, -N(RB)C(0)C(RIR 2 )N(R 5 )-T-R D ,
  • G is C 5 -C 6 carbocycle or 5- to 6-membered
  • heterocycle such as , and is optionally substituted with one or more RA (e.g., one or more chloro or bromo).
  • E preferably is a 7- to 12-
  • membered bicycle such as 3 ⁇ 4o u , wherein U is independently selected at each occurrence from -(CH 2 )- or -(NH)-; V and Z 2 o are each independently selected from Ci-C 4 alkylene, C2-C 4 alkenylene or C 2 -C 4 alkynylene, in which at least one carbon atom can be independently optionally replaced with O, S or N), and is independently optionally substituted with one or more R A . More preferably, Ri is R c , and R 2 and R 5 , taken together with the atoms to which they are attached, form a 5- to 6-membered
  • R A is optionally substituted with one or more R A (such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C 6 alkyl (e.g., methyl), or C 2 -C 6 alkenyl (e.g., allyl)); and R 3 and R 6 are each independently Rc, and R4 and R7, taken together with the atoms to which they are attached, form a 5-
  • R A such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C 6 alkyl (e.g., methyl), or C 2 -C 6 alkenyl (e.g., allyl)
  • R 3 and R 6 are each independently Rc, and R4 and R7, taken together with the atoms to which they are attached, form a 5-
  • 6-membered carbocycle/heterocycle or 6- to 12-membered bicycle e.g.,
  • R A which is optionally substituted with one or more R A (such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C 6 alkyl (e.g., methyl), or C 2 -C 6 alkenyl (e.g., allyl)).
  • R A such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C 6 alkyl (e.g., methyl), or C 2 -C 6 alkenyl (e.g., allyl)).
  • Y can also be selected from -M-C(RIR 2 )N(R 5 )-C(0)-LY'-M'-R D , -M-C(RIR 2 )N(R 5 )-L Y '- M'-R D , -L S -C(RIR 2 )N(R 5 )-C(0)-LY'-M'-R D , -L S -C(RIR 2 )N(R 5 )-L Y '-M'-R D , -M- C(R3R4)C(R 6 R 7 )-C(0)-LY'-M'-R D , -M-C(R3R4)C(R6R 7 )-LY'-M'-R D , -L S -C(R 3 R4)C(R 6 R 7 )-C(0)- LY'-M'-R d , or -L S -C(R 3 R4)C(R 6 R 7 )-
  • R L is a substituent such as, but not limited to phenyl, -SMe, or methoxy.
  • Any stereochemistry at a carbon within the group L Y ' can be either (R) or (S). More preferably, Ri is R c , and R 2 and R 5 , taken together with the atoms to which they are attached, form a 5- to 6-membered heterocycle or 6- to 12- membered bicycle (e.g., which is optionally substituted with one or more RA (e.g., one or more hydroxy); and R3 and R6 are each independently Rc, and R4 and R 7 , taken together with the atoms to which they are attached, form a 5- to 6-membered carbocycle/heterocycle
  • Y is selected from -N(RB)CO-C(RIR2)N(R 5 )-C(0)-LY'-N(RB)C(0)0-R D , - N(RB)CO-C(R 1 R 2 )N(R 5 )-C(0)-L Y '-N(RB)C(0)-R D , -N(RB)CO-C(R 1 R 2 )N(R 5 )-C(0)-L Y '- N(R B )S(0) 2 -R D , -N(RB)CO-C(R 1 R 2 )N(R 5 )-C(0)-L Y '-N(RBRB')-RD, -N(RB)CO-C(R!R 2 )N(R 5 )- C(0)-L Y '-0-R D , -N(R B )CO-C(R 1 R 2 )N(R 5 )-C(0)-L Y '-R D , -N(R B
  • 6-membered heterocycle or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more RA; and R 3 and R6 may be each independently R C , and R4 and R 7 , taken together with the atoms to which they are attached, may form a 5- to 6-membered
  • Y is selected from -N(R B ")CO-C(R I R 2 )N(R 5 )-C(0)-L Y -N(R B ")C(0)- L S -R E or -C(R 1 R 2 )N(R 5 )-C(0)-L Y -N(R B ")C(0)-L s -R E , or Y is -G-C(R !
  • R 2 N(R5)-C(0)-L Y - N(R B ")C(0)-L s -R E , wherein L Y is Ci-C 6 alkylene optionally substituted with one or more R L , and R B " is each independently R B .
  • R B " and Ri are each preferably hydrogen or Ci-C 6 alkyl, and R 2 and R 5 , taken together with the atoms to which they are attached, preferably form a 5- to 6-membered
  • heterocycle or 6- to 12-membered bicycle e.g., which is optionally substituted with one or more R A (such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C 6 alkyl (e.g., methyl), or C 2 -Cealkenyl (e.g., allyl)).
  • R A such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C 6 alkyl (e.g., methyl), or C 2 -Cealkenyl (e.g., allyl)).
  • L Y is Ci-Cealkylene substituted with one or more R L such as a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 - Cealkenyl, C 2 -C 6 alkynyl, Ci-Cehaloalkyl, C 2 -Cehaloalkenyl or C 2 -C 6 haloalkynyl.
  • R L such as a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thio
  • i-C 6 alkylene such as, but not limited to, , or (stereochemistry at a carbon within the group L Y can be either (R) or (S)), L Y is independently optionally substituted with one or more R L (e.g., one or more phenyl or methoxy), G
  • H preferably is — ,J , R B " is hydrogen; -C(RiR 2 )N(R 5 )- is ⁇ ; L s is a bond; and R E is methoxy.
  • Non-limiting examples of preferred Y include:
  • T and R D are as defined herein.
  • T for example, can be -L s -M-Ls'-M'-L s "- w L s is a bond;
  • M is C( ' is Ci-C 6 alkylene such as, but not limited to, , , or , where L s ' is independently optionally substituted with one or more R L ;
  • R L is a substituent such as, but not limited to phenyl or methoxy;
  • M' is -NHC(O)- or -NMeC(O)-; and L s " is a bond.
  • Any stereochemistry at a carbon within the group L s ' can be either (R) or (S).
  • R D for example, can be -L s -M-Ls'-M'-L s "- w L s is a bond;
  • M is C( ' is Ci-C 6 alkylene such as, but not limited to, , ,
  • T-R D includes, but is not limited to:
  • T-R D may also include certain stereochemical configurations; thus T-R D includes, but is not limited
  • Non-limiting examples of preferred Y also include:
  • Z is preferably selected from -L S -C(R 8 R 9 )N(R 12 )-T-RD, -L S -C(RIORII)C(RI 3 RI4)-T-RD, - G-C(R 8 R 9 )N(R 12 )-T-R D , -G-C(R 10 R hinder)C(R 13 R I 4)-T-R D , -N(R B )C(0)C(R 8 R 9 )N(R 12 )-T-R D , - N(RB)C(O)C(R 10 Rn)C(R 13 Ri4)-T-RD, -C(0)N(R B )C(R 8 R 9 )N(R 12 )-T-R D ,
  • C(O)N(RB)C(R 10 Rn)C(R 13 Ri4)-T-RD, -N(R B )C(0)-L S -E, or -C(0)N(R B )-L S - G is C 5 -
  • C 6 carbocycle or 5- to 6-membered heterocycle such as , and is optionally substituted with one or more R A (e.g., one or more chloro or bromo).
  • R A e.g., one or more chloro or bromo
  • E preferably is a 8- to 12-membered bicycle (such as wherein U is independently selected at each occurrence from -(CH 2 )- or -(NH)-; and V and Z 20 are each independently selected from Ci-C4alkylene, C2-C4alkenylene or C2-C4alkynylene, in which at least one carbon atom is independently optionally replaced with O, S or N), and is independently optionally substituted with one or more R A . More preferably, R 8 is Rc, and R9 and R12, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,
  • R A such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-Cealkyl (e.g., methyl), or C 2 -C 6 alkenyl (e.g., allyl)
  • R A such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-Cealkyl (e.g., methyl), or C 2 -C 6 alkenyl (e.g., allyl)
  • Rio and R13 are each independently R c , and Rn and R M , taken together with the atoms to which th
  • R A such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C 6 alkyl (e.g., methyl), or C 2 -C 6 alkenyl (e.g., allyl)).
  • R A such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C 6 alkyl (e.g., methyl), or C 2 -C 6 alkenyl (e.g., allyl)).
  • Z can also be selected from -M-C(R 8 R 9 )N(R 12 )-C(0)-L Y '-M'-R D , -M-C(R 8 R 9 )N(R 12 )-L Y '- M'-R D , -L s -C(R 8 R 9 )N(R 12 )-C(0)-L Y '-M'-R D , -L S -C(R 8 R 9 )N(R 12 )-L Y '-M'-R D , -M- C(R 10 Rn)C(R 13 Ri 4 )-C(O)-L Y '-M'-R D , -M-C(R 10 R hinder)C(R 13 Ri4)-L Y '-M'-R D , -L s -
  • M preferably is bond, -C(0)N(R B )- or -N(R B )C(0)-, M' preferably is bond, -C(0)N(R B )-, - N(R B )C(0)-, -N(R b )C(0)0-, N(R B )C(0)N(R B ')- -N(R b )S(0)- or -N(R B )S(0) 2 -, and L Y ' preferably is Ci-C 6 alkylene which is independently optionally substituted with one or more R L .
  • L Y ' for example, ealkylene such as, but not limited to, , or ; and the optional R L is
  • Any stereochemistry at a carbon within the group L Y ' can be either (R) or (S). More preferably, R 8 is Rc, and R 9 and R 12 , taken together with the atoms to which they are attached,
  • 6-membered heterocycle or 6- to 12-membered bicycle e.g., or which is optionally substituted with one or more R A (e.g., one or more hydroxy); and Rio and R 13 are each independently R c , and Rn and R 14 , taken together with the atoms to which they are attached, form a 5- to 6-membered carbocycle/heterocycle or 6- to 12-membered bicycle (e.g., is optionally substituted with one or more R A .
  • Z is selected from -N(RB)CO-C(R 8 R 9 )N(R 12 )-C(0)-LY'-N(RB)C(0)0-R D ,
  • R 8 may be Rc, and R 9 and Ri 2 , taken together with the atoms to which they are attached, may form a 5- to 6-membered heterocycle or 6- to 12-membered
  • Rio and R13 may be each independently Rc, and Rn and R14, taken together with the atoms to which they are attached, may form a 5- to 6-membered carbocycle/heterocycle or 6- to 12-membered bicycle
  • Z is selected from -N(RB")CO-C(R 8 R 9 )N(R 12 )-C(0)-LY-N(RB")C(0)- L S -R E or -C(R 8 R 9 )N(R 12 )-C(0)-L Y -N(RB")C(0)-L S -R e , or Z is -G-C(R 8 R 9 )N(R 12 )-C(0)-L Y - N(R B ")C(0)-L S -R E , wherein L Y is Ci-C 6 alkylene optionally substituted with one or more R L , and R B " is each independently R B .
  • R B " and R 8 are each preferably hydrogen or Ci-C 6 alkyl, and R 9 and R12, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered
  • heterocycle or 6- to 12-membered bicycle e.g., which is optionally substituted with one or more R A (such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C 6 alkyl (e.g., methyl), or C 2 -C 6 alkenyl (e.g., allyl)).
  • R A such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C 6 alkyl (e.g., methyl), or C 2 -C 6 alkenyl (e.g., allyl)).
  • L Y is Ci-C 6 alkylene substituted with one or more R L such as a C3-Cecarbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 - Cealkenyl, C 2 -C 6 alkynyl, Ci-Cehaloalkyl, C 2 -Cehaloalkenyl or C 2 -C 6 haloalkynyl.
  • R L such as a C3-Cecarbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thio
  • i-C 6 alkylene such as, but not limited to, , or (stereochemistry at a carbon within the group L Y can be either (R) or (S)); L Y is independently optionally substituted with one or more R L (e.g., one or more phenyl or methoxy); G
  • T and R D are as defined herein.
  • T for example, can be -L s -M-Ls'-M'-L s "- w L s is a bond;
  • M is C( ' is Ci-C 6 alkylene such as, but not limited to, , , or , where L s ' is independently optionally substituted with one or more R L ; the optional R L is a substituent such as, but not limited to phenyl or methoxy;
  • M' is -NHC(O)- or - NMeC(O)-; and L s " is a bond.
  • Any stereochemistry at a carbon within the group L s ' can be either
  • R D for example is methoxy.
  • T-R D includes, but is not limited to: .
  • T-R D may also include certain stereochemical configurations; thus T-R D includes,
  • T can be, without limitation, independently selected at each occurrence from -C(0)-L s '-, - C(0)0-L S '-, -C(0)-L S '-N(RB)C(0)-L S "-, -C(0)-L S '-N(R B )C(0)0-L S "-, -N(R B )C(0)-L S '- N(RB)C(0)-L S "-, -N(RB)C(0)-L S '— N(RB)C(0)0-L s "-, or -N(R B )C(0)-L S '— N(R B )-L S "-.
  • T is independently selected at each occurrence from -C(0)-L s '-M'-L s "- or - N(R B )C(0)-L s '-M'-L s "-. More preferably, T is independently selected at each occurrence from - C(0)-L S '-N(RB)C(0)-L s "- or -C(0)-L S '-N(R B )C(0)0-L S "-.
  • R T is a substituent selected from -Ci-C 6 alkyl, -C 2 -C 6 alkenyl, -Ci-C 6 alkyl-OH, -Ci-C 6 alkyl-0-Ci- C 6 alkyl, 3- to 6-membered heterocycle (e.g., tetrahydrofuranyl), or C 3 -C 6 carbocyclyl (e.g., phenyl, cyclohexyl); M' is -NHC(O)-, -N(Et)C(0)- or -N(Me)C(0)-; and L s " is a bond.
  • R D preferably is hydrogen, -Ci-C 6 alkyl (e.g., methyl), -0-Ci-C 6 alkyl (e.g., methoxy, tert-butoxy), methoxymethyl, or -Nid-Cealkyfh (e.g., -NMe 2 ).
  • R D can be either (R) or (S).
  • T can also be, without limitation, -L s -M-L s '- where L s is a bond; M is C(O); L s ' is d-
  • Cealkylene (e.g., ) where L s ' is independently optionally substituted with R T ; the optional
  • R T is a substituent selected from -Ci-C 6 alkyl, -Ci-C 6 alkyl-OH, -Ci-C 6 alkyl-0-Ci-C 6 alkyl, or a C 3 - C 6 carbocyclyl (e.g., phenyl, cyclohexyl).
  • R D for example is -OH; -OC(0)Me; -NH(Ci-C 6 alkyl) (e.g., -NHMe, -NHEt); -N(Ci-C 6 alkyl) 2 (e.g., -NMe 2 , -NEt 2 ); a 3- to 10-membered heterocyclyl (e.g., pyrrolidinyl, imidazolidinyl, hexahydropyrimidinyl, mo holinyl, piperidinyl) optionally substituted with one or more halogen, oxo; C 3 -Ci 0 carbocycle (e.g., cyclopentyl) optionally substituted with -OH; -Ci-C 6 alkyl (e.g., isopropyl, 3-pentyl) optionally substituted with -OH; or NHR T where R T is a 3- to 6-membered heterocyclyl (e.g.,
  • stereochemistry at a carbon within the group T-RD can be either (R) or (S).
  • L K can also be independently selected at each occurrence from a bond; -L s '-N(R B )C(0)-L s -; -L s '-C(0)N(R B )-L s -; or C C 6 alkylene, C 2 -C 6 alkenylene, C 2 - C 6 alkynylene, C 3 -Ci 0 carbocycle or 3- to 10-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, R T> - 0-R s , -S-Rs, -N(R S R S '), -OC(0)R s , -C(0)OR s , nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano, wherein R T , R B , Rs, Rs', L s and L s ' are as defined above
  • R A preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-Cealkyl, C 2 -C6alkenyl or C 2 - Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C 3 -C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro,
  • R A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C 3 -C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C 2
  • R A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.
  • L s , L s ' and L s " preferably are each independently selected at each occurrence from bond; or Ci-C 6 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene.
  • a and B can be the same or different.
  • Li and L 2 , or Y and Z, or Y-A- and Z-B-, or -A-Li- and -B-L 2 - can be the same or different.
  • Y-A-Li- is identical to Z- B-L 2 -.
  • Y-A-Li- is different from Z-B-L 2 -.
  • X is 5- or 6-membered carbocycle or heterocycle or 6- to 12-membered bicycle
  • D is C 5 -C6carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more R A , or is substituted with J and optionally substituted with one or more R A , wherein J is C3-C 6 carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R A .
  • J is substituted with a C 3 -C 6 carbocycle or 3- to 6- membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 - C 6 haloalkynyl, C(0)OR s or -N(R S R S '), J can also be optionally substituted with one or more R A .
  • substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6
  • D is or , wherein R M and R N are as defined above.
  • D is wherein J and R N are as defined above.
  • Li and L 2 are each independently bond or Ci-C 6 alkylene, and L 3 is bond, Ci-C 6 alkylene or -C(O)-, and Li, L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • Li, L 2 , and L 3 are bond.
  • Y is -N(R B )C(0)C(RiR 2 )N(R 5 )-T-R D , or -N(R B )C(0)C(R 3 R4)C(R6R7)-T-RD, and Z is -
  • Ri is R c , and R 2 and R 5 , taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring
  • R3 and R 6 are each independently R c , and R4 and R 7 , taken together with the atoms to which they are attached, form a 5-
  • RS is Rc, and R9 and R12, taken together with the atoms to which they are
  • T is preferably independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)-L s "- or -C(O)- L Y '-N(R B )C(0)0-L s "-.
  • L Y ' is each independently L s ' and, preferably, is each independently Ci-
  • C 6 alkylene e.g., -CH 2 - or or optionally substituted with one or more substituents selected from R L .
  • T can also be, without limitation, selected from -C(0)-L Y '-L s "-, -C(0)-L Y '-0- Ls"- -C(0)-L Y '-N(R B )-L s "-, or -C(0)-L Y '-N(R B )S(0) 2 -L s "-.
  • R D includes (1) -0-Ci-C 6 alkyl, -0-C 2 -C 6 alkenyl, -0-C2-C 6 alkynyl, Ci-C 6 alkyl, C 2 - Cealkenyl or C2-Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C 3 -C 6 carbocycle or 3- to 6-membered heterocycle; or (2) C3-C 6 carbocycle or 3- to 6-membered heterocycle each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
  • a is nd is optionally substituted with one or more R A ; B is 0 r and is optionally substituted with one or more R A .
  • Zi is independently selected at each occurrence from O, S, NH or CH 2 ; and Z 2 is independently selected at each occurrence from N or CH.
  • a is and A and B are substituted with one or more halogen, such as F or CI.
  • a and/or B are halo-substituted benzimidazole (e.g., A is
  • the compounds of this embodiment can have significantly improved pharmacokinetic properties as well as improved inhibitory activity against certain HCV genotype la mutants, as compared to the same compounds but with unsubstituted benzimidazole.
  • X is 5- or 6-
  • D is C 5 -C 6 carbocycle or 5- to 6- membered heterocycle (e.g., phenyl), and is optionally substituted with one or more R A , or is substituted with J and optionally substituted with one or more R A , wherein J is C 3 -C 6 carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R A .
  • J is substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or - N(R S R S '), and J can also be optionally substituted with one or more R A .
  • D is s wherein R M and R N are as defined above. Also preferably, D is
  • Li and L 2 are each independently bond or Ci-C 6 alkylene, and L 3 is bond, Ci-C 6 alkylene or -C(O)-, and L L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • L u L 2 , and L 3 are bond.
  • Y is - L S -C(R 1 R 2 )N(R 5 )-T-R D or -L S -C(R 3 R4)C(R 6 R 7 )-T-R D
  • Z is -L S -C(R 8 R 9 )N(R 12 )-T-R D or -L s - C(RioRn)C(Ri 3 Ri4)-T-R D .
  • Ri is Rc, and R 2 and R 5 , taken together with the atoms to which they are
  • a 5- to 6-membered heterocyclic ring e.g., which is optionally substituted with one or more RA;
  • R3 and R6 are each independently Rc, and R4 and R7, taken together with the atoms to which the are attached, form a 5- to 6-membered carbocyclic or heterocyclic ring
  • RS is Rc, and R9 and Ri 2 , taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring which is optionally substituted with one or more RA; and Rio and Ri 3 are each independently R c , and Rn and R14, taken together with the atoms to which they are attached, form a
  • T is preferably independently selected at each occurrence from -C(0)-L Y '- N(R B )C(0)-Ls"- or -C(0)-L Y '-N(R B )C(0)0-Ls"-.
  • L Y ' is each independently L s ' and, preferably, is independently Ci-C 6 alkylene (e.g., -CH 2 -) and optionally substituted with one or more substituents selected from R L .
  • T can also be, without limitation, selected from -C(0)-L Y '-L s "-, -C(0)-L Y '-0- Ls"-, -C(0)-L Y '-N(R B )-Ls"-, or -C(0)-L Y '-N(R B )S(0) 2 -L s "-.
  • R D include (1) -O-Ci-Cealkyl, -(XVCealkenyl, -0-C 2 -C6alkynyl, Ci-Cealkyl, C2- Cealkenyl or C2-Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C 3 -C 6 carbocycle or 3- to 6-membered heterocycle; or (2) C3-C 6 carbocycle or 3- to 6-membered heterocycle each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, ox
  • X is 5- or 6-membered carbocycle
  • D can be, for example, C 5 -C 6 carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more R A , or is substituted with J and optionally substituted with one or more RA, wherein J is C3-C 6 carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA.
  • J is substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C2-C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C2-C 6 haloalkynyl, C(0)OR S or - N(R S R S '), and J can also be optionally substituted with one or more R A .
  • D is s wherein R M and R N are as defined above. Also preferably, D is
  • Li and L 2 are each independently bond or Ci-C 6 alkylene, and L 3 is bond, Ci-C 6 alkylene or -C(O)-, and L L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • L u L 2 , and L 3 are bond.
  • Y is - G-C(RiR 2 )N(R 5 )-T-R D or -G-C(R 3 R 4 )C(R 6 R 7 )-T-R D
  • Z is -G-C(R 8 R 9 )N(R 12 )-T-R D or -G- C(RioRn)C(Ri 3 Ri 4 )-T-R D
  • G is independently C 5 -C 6 carbocycle or 5- to 6-membered heterocycle, such as , and is independently optionally substituted with one or more R A .
  • Ri is Rc, and R 2 and R 5 , taken together with the atoms to which they are attached, form a 5- to 6-
  • membered heterocyclic ring e.g., which is optionally substituted with one or more R A ;
  • R 3 and R6 are each independently R C , and R4 and R 7 , taken together with the atoms to which they are
  • R S is Rc, and R9 and Ri 2 , taken together with the atoms to
  • heterocyclic ring e.g., ch is optionally substituted with one or more R A .
  • T is preferably independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)-Ls"- or -C(O)- L Y '-N(R B )C(0)0-L s "-.
  • L Y ' is each independently L s ' and, preferably, is each independently Ci- Cealkylene (e.g., -CH 2 - or ) and optionally substituted with one or more substituents selected from R L .
  • T can also be, without limitation, selected from -C(0)-L Y '-L s "-, -C(0)-L Y '-0- Ls"- -C(0)-L Y '-N(R B )-L s "-, or -C(0)-L Y '-N(RB)S(0) 2 -L s " one of Y
  • R D include (1) -0-Ci-C 6 alkyl, -O- C 2 -C 6 alkenyl, -0-C 2 -C 6 alkynyl, Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C 3 -C 6 carbocycle or 3- to 6-membered heterocycle; or (2) C3-C 6 carbocycle or 3- to 6-membered heterocycle each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphonoxy, phosphonoxy, phosphonoxy,
  • X is 5- or 6-membered carbocycle or
  • heterocycle or 6- to 12-membered bicycle e.g., wherein X 3 is N and is directly linked to -L 3 -D
  • R A is optionally substituted with one or more R A .
  • D can be, for example, C 5 -C 6 carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more R A , or is substituted with J and optionally substituted with one or more RA, wherein J is C3-C 6 carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA.
  • J is substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or - N(R S R S '), and J can also be optionally substituted with one or more R A .
  • D is
  • Li and L 2 are each independently bond or Ci-C 6 alkylene, and L 3 is bond, Ci-C 6 alkylene or -C(O)-, and L L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • L u L 2 , and L 3 are bond.
  • Y is - N(RB)C(0)C(RIR 2 )N(R 5 )-T-R d or -N(R b )C(0)C(R 3 R4)C(R 6 R7)-T-RD
  • Z is -G-C(R 8 R 9 )N(Ri 2 )- T-R D or -G-C(RioRn)C(Ri 3 Ri 4 )-T-R D
  • Y is -G-C(RiR 2 )N(R 5 )-T-R D or -G-C(R 3 R4)C(R 6 R 7 )-T- R D
  • Z is -N(R B )C(0)C(R 8 R 9 )N(R 12 )-T-R D or -N(RB)C(O)C(R 10 Rn)C(R 13 R 14 )-T-RD.
  • 3 ⁇ 4 is R c , and R 2 and R 5 , taken together with the atom
  • eterocyc c r ng e.g., w c s opt ona y su st tute w t one or more R A ;
  • RS is Rc, and R9 and Ri 2 , taken together with the atoms to which
  • a 5- to 6-membered heterocyclic ring e.g., which is optionally substituted with one or more RA; and Rio and Ri 3 are each independently R c , and Rn and R 14 , taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g., which is optionally substituted with one or more R A . independently C 5 -C 6 carbocycle or 5- to 6-membered heterocycle, such as
  • T is preferably independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)-Ls"- or -C(0)-L Y '-N(R B )C(0)0-Ls"-.
  • ' is each independently L s ' and, preferably, is each independently Ci-C 6 alkylene (e.g., -CH 2 - or ) and optionally substituted with one or more substituents selected from R L .
  • T can also be, without limitation, selected from -C(0)-L Y '-L s "-, -C(0)-L Y '-0-L s "-, -C(0)-L Y '-N(R B )-L s "-, '-N(R B )S(0) 2 -L s "-.
  • Y is as described above,
  • A is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl
  • a and B are each independently optionally substituted with one or more R A .
  • Zi is independently selected at each occurrence from O, S, NH or CH 2 ; and Z 2 is independently selected at each occurrence from N or CH.
  • X is 5- or 6-membered carbocycle or heterocycle or 6- to 12-membered bicycle (e.g.,
  • X 3 is N and is directly linked to -L 3 -D) and is optionally substituted with one or more R A .
  • D is C 5 -C 6 carbocycle or 5- to 6- membered heterocycle (e.g., phenyl), and is optionally substituted with one or more R A , or is substituted with J and optionally substituted with one or more R A , wherein J is C3-Cecarbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R A .
  • J is substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or - N(R S R S '), and J can also be optionally substituted with one or more R A .
  • D is
  • Li and L 2 are each independently bond or Ci-C 6 alkylene, and L 3 is bond, Ci-C 6 alkylene or -C(O)-, and L L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • L u L 2 , and L 3 are bond.
  • Y is N(RB)C(0)C(R!R 2 )N(R 5 )-T-R D , -N(R B )C(0)C(R 3 R4)C(R 6 R 7 )-T-R D , -G-C(R!R 2 )N(R 5 )-T-R d or - G-C(R 3 R4)C(R 6 R 7 )-T-R D
  • Z is -L S -C(R 8 R 9 )N(R 12 )-T-R D or
  • B is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl
  • Ri is Rc, and R2 and R 5 , taken together with the atoms to which they are attached, form a 5- to 6-
  • membered heterocyclic ring e.g., which is optionally substituted with one or more RA;
  • R 3 and R6 are each independently R C , and R4 and R 7 , taken together with the atoms to which they are
  • RS is Rc, and R9 and R12, taken together with the atoms to
  • heterocyclic ring e.g., optionally substituted with one or more R A .
  • G is independently C 5 -C 6 carbocycle or 5- to 6-membered heterocycle, such as
  • T is preferably independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)-L s "- or -C(0)-L Y '-N(R B )C(0)0-L s "-.
  • ' is each independently L s ' and, preferably, is each independently Ci-Cealkylene (e.g., -CH 2 - or ) and optionally substituted with one or more substituents selected from R L .
  • T can also be, without limitation, selected from -C(0)-L Y '-L s "-, -C(0)-L Y '-0-L s "-, -C(0)-L Y '-N(R B )-L s "-, or -C(0)-L Y '-N(R B )S(0) 2 -L s "-.
  • A is 5- or 6-membered carbocycle or
  • the present invention also features compounds of Formulae I, I A , 3 ⁇ 4, Ic and I D as described herein (including each embodiment described hereunder) and pharmaceutically acceptable salts thereof, wherein:
  • D is C 3 -Ci 2 carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with one or more R A ; or D is C 3 -Ci 2 carbocycle or 3- to 12-membered heterocycle which is substituted with J and optionally substituted with one or more R A , where J is C 3 - Ci 5 carbocycle or 3- to 15-membered heterocycle (e.g., a 3- to 6-membered monocycle, a 6- to 12-membered fused, bridged or spiro bicycle, a 10- to 15-memberd tricycle containing fused, bridged or spiro rings, or a 13- to 15-membered carbocycle or heterocycle) and is optionally substituted with one or more R A , or J is -SF 5 ; or D is hydrogen or R A ;
  • R A is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L B -RE; wherein two adjacent R A , taken together with the atoms to which they are attached and any atoms between the atoms to which they are attached, can optionally form carbocycle or heterocycle;
  • L B is independently selected at each occurrence from L s ; or Ci-Ci 0 alkylene, C 2 -Ci 0 alkenylene or C2-Cioalkynylene, each of which optionally has 1 , 2, 3, 4 or 5 carbon atoms indenpdently replaced with O, S or N(R B ), and each of said Ci-Cioalkylene, C 2 - Ci 0 alkenylene or C 2 -Cioalkynylene being independently optionally substituted with one or more R L ;
  • R E is independently selected at each occurrence from -0-R s , -S-R s , -C(0)R s , -OC(0)R s , - C(0)OR s , -N(RsRs'), -S(0)R s , -S0 2 R s , -C(0)N(R s R s '), -N(R s )C(0)R s ', - N(Rs)C(0)N(R s 'Rs"), -N(R s )S0 2 R s ', -S0 2 N(R s R s '), -N(R s )S0 2 N(R s 'R s "), - N(Rs)S(0)N(R s 'Rs"), -OS(0)-R s , -OS(0) 2 -R s , -S(0) 2 OR s , -S(0)OR s ,
  • R L is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, -0-R s , -S-R s , -C(0)R s , -OC(0)R s , -C(0)OR s , -N(R S R S '), - S(0)R s , -S0 2 R s , -C(0)N(R s R s ') or -N(R s )C(0)R s ' ; or C 3 -Ci 2 carbocycle or 3- to 12- membered heterocycle (e.g., C 3 -C 6 carbocycle or 3- to 6-membered heterocycle), each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thi
  • a and B are each independently 5- or 6-membered carbocycle or heterocycle (preferably, A and B are each independently phenyl such as and are each independently optionally substituted with one or more RA (preferably, A and B are each independently substituted with at least one halo such as F).
  • X is 5- or 6-membered carbocycle or heterocycle or 6- to
  • D is a C 5 -C 6 carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is substituted with J and optionally substituted with one or more R A .
  • J is C 3 -C 6 carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle, or 13- to 15-membered carbocycle/heterocycle, and J is optionally substituted with one or more R A .
  • J is substituted with a C 3 -C 6 carbocycle, 3- to 6-membered heterocycle, 6- to 12- membered bicycle or 7- to 12-membered carbocycle/heterocycle, which is independently optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, -C(0)OR s or -N(R S R S '), or (2) trimethylsilyl, -0-R s , -S-R s , -C(0)R s ; and J can also be optionally substituted with one
  • D is or •n b v , wherein J is as defined above, and each R N is independently selected from R D and preferably is hydrogen or halo such as F.
  • Li and L 2 are each independently bond or Ci-C 6 alkylene, and L 3 is bond, Ci-C 6 alkylene or -C(O)-, and L u L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • Li, L 2 , and L 3 are bond.
  • Y is -N(RB)C(0)C(R!R 2 )N(R 5 )-T-R D , -N(R B )C(0)C(R 3 R4)C(R 6 R 7 )-T-R D , -G-C(R!R 2 )N(R 5 )-T-R D or -G-C(R 3 R4)C(R 6 R 7 )-T-R D .
  • Z is -N(R B )C(0)C(R 8 R 9 )N(R 12 )-T-R D ,
  • Ri is Rc; and R 2 and R 5 , taken together with the atoms to which they are attached, form a 5- to 6-
  • membered heterocyclic ring e.g., or 6- to 12-membered bicycle (e.g.,
  • R 3 and R6 are each independently R C , and R4 and R7, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or
  • heterocyclic ring e.g., 6- to 12-membered bicycle which is optionally substituted with one or more RA.
  • RS is Rc; and R9 and Ri 2 , taken together with the atoms to which they are
  • R A e.g., which is optionally substituted with one or more R A
  • Rio and Ri 3 are each independently R c , and Rn and R14, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g., or 6- to 12-membered bicycle which is optionally substituted with one or more R .
  • G is independently C 5 -C 6 carbocycle or 5- to 6- membered heterocycle, such as and is independently optionally substituted with one or more R A .
  • T is preferably independently selected at each occurrence from -C(0)-L Y '- N(R B )C(0)-L S "- or -C(0)-L Y '-N(R B )C(0)0-L S "- ' is each independently L S ' and, preferably, is each independently Ci-C 6 alkylene (e.g., -CH 2 - or ) and optionally substituted with one or more substituents selected from R L .
  • Ci-C 6 alkylene e.g., -CH 2 - or
  • T can also be, without limitation, selected from -C(0)-L Y '-L s "- '-0-L s "-, -C(0)- '-N(R B )-L s "-, or -C(0)-L Y '-N(R B )S(0) 2 -L s "-.
  • Y Y
  • A is and is optionally substituted with one or more R A ; B is or , and is optionally substituted with one or more R A .
  • Zi is independently selected at each occurrence from O, S, NH or CH 2 ; and Z 2 is independently selected at each occurrence from N or CH.
  • a and B are each independently substituted with at least one halo such as F.
  • a is B is and A and B are substituted with one or more halogen, such as F or CI.
  • halo-substituted benzimidazole e.g., A is and B is
  • the compounds of this embodiment can have significantly improved pharmacokinetic properties as well as improved inhibitory activity against certain HCV genotype la mutants, as compared to the same compounds but with unsubstituted benzimidazole.
  • X is 5- or 6-
  • X 3 is N and is directly linked to -L 3 -D), and is optionally substituted with one or more RA.
  • D is a C 5 -C 6 carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is substituted with J and optionally substituted with one or more R A .
  • J is C 3 -C 6 carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle or 13- to 15-membered carbocycle/heterocycle, and J is optionally substituted with one or more R A .
  • J is substituted with a C 3 - Cecarbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle or 7- to 12-membered carbocycle/heterocycle, which is independently optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 - Cehaloalkynyl, -C(0)OR S or -N(R S R S '), or (2) trimethylsilyl, -0-R S , -S-R S , or -C(0)R S ; and J can
  • D is
  • Li and L 2 are each independently bond or Ci-C 6 alkylene, and L 3 is bond, Ci-C 6 alkylene or -C(O)-, and L u L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • L u L 2 , and L 3 are bond.
  • Y is -L s -C(RiR 2 )N(R 5 )-T-R D or -L s - C(R 3 R4)C(R 6 R 7 )-T-R D .
  • Z is 3 ⁇ 4 is R c ; and R 2 and R 5 , taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (e.g., or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more RA; R3 and R6 are each independently R C , and R4 and R 7 , taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or
  • heterocyclic ring e.g., or 6- to 12-membered bicycle which is optionally substituted with one or more RA.
  • RS is Rc; and R9 and R12, taken together with the atoms to which they are
  • R A (e.g., which is optionally substituted with one or more R A ; and Rio and R43 are each independently R c , and Rn and R14, taken together with the atoms to which they are attached, form a
  • T is preferably independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)-L s "- or -C(0)-L Y '-N(R B )C(0)0-L s "-.
  • L Y ' is each independently L s ' and, preferably, is each independently Ci-C 6 alkylene (e.g., -CH 2 - or ) and optionally substituted with one or more substituents selected from R L .
  • T can also be, without limitation, selected from -C(0)-L Y '-L s "-, -C(0)-L Y '-0-L s "-, -C( -L Y '-N(R B )-L s "-, or -
  • R D include (1) -0-Ci-C 6 alkyl, -0-C 2 -
  • the present invention features compounds of Formula IA and pharmaceutically acceptable salts thereof.
  • R N B is each independently selected from R B ;
  • Rc' is each independently selected from R c ;
  • R D ' is each independently selected from R D ;
  • R 2 and R 5 taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more R A ;
  • R 9 and Ri 2 taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more R A ;
  • A, B, D, X, Li, L 2 , L 3 , T, R A , RB, RC, and R D are as described above in Formula I.
  • D preferably is selected from C 5 -C 6 carbocycle, 5- to 6-membered heterocycle, or 8- to 12- membered bicycles, and is optionally substituted with one or more RA.
  • D can also be preferably selected from Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, and is optionally substituted with one or more R L .
  • D is C 5 -C 6 carbocycle, 5- to 6-membered heterocycle, or 6- to 12- membered bicycles, and is substituted with one or more R M , where R M is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L S -R E .
  • R M is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L S -R E .
  • D is phenyl, and is optionally substituted with one or more R A . More preferably, D is phenyl, and is substituted with one or more
  • R M wherein R M is as defined above.
  • D is wherein R M is as defined above, and each R N is independently selected from R D and preferably is hydrogen.
  • R N can also preferably be halo such as F.
  • D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or more RA. More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or
  • D is , wherein R M is as defined above, and each R N is independently selected from R D and preferably is hydrogen.
  • R N can also preferably be halo such as F.
  • D is also preferably indanyl, 4,5,6,7- tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl, and is optionally substituted with one or more RA.
  • D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l ,3]dioxol-5-yl, and is substituted with one or more R M .
  • D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l ,3]dioxol-5-yl, and is substituted with one or more R M .
  • D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l ,3]dioxol-5-yl, and is substituted with one or more R M .
  • D is indanyl, 4,5,6,
  • R M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-Cecarbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-
  • R M is halogen, hydroxy, mercapto, amino, carboxy; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 - Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.
  • R M is Ci-C 6 alkyl which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.
  • R M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or R M is -L S -R E , wherein L s is a bond or Ci-C 6 alkylene, and R E is - N(R S R S '), -O-Rs, -C(0)R s , -C(0)OR s , -C(0)N(R s R s '), -N(R s )C(0)R s ', -N(R s )C(0)OR s ', - N(R s )S0 2 R s ', -S0 2 R s , -SRs, or -P(0)(OR s ) 2 , wherein R s and R s ' can be, for example, each independently selected at each occurrence from (1) hydrogen or (2) Ci-Ceal
  • R M is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or Ci-C 6 alkyl (e.g., methyl, isopropyl, tert-butyl), C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy.
  • halogen e.g., fluoro, chloro, bromo, iodo
  • hydroxy, mercapto, amino, carboxy or Ci-C 6 alkyl (e.g., methyl, isopropyl, tert-butyl), C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituent
  • R M is CF 3 , - C(CF 3 ) 2 -OH, -C(CH 3 ) 2 -CN, -C(CH 3 ) 2 -CH 2 OH, or -C(CH 3 ) 2 -CH 2 NH 2 .
  • R M is -L s - R E where L s is a bond and R E is -N(R S R S ), -0-R s , -N(R s )C(0)OR s ', -N(R s )S0 2 R s ', -S0 2 R s , or - SR S .
  • R E is -N(Ci-C 6 alkyl) 2 (e.g., -NMe 2 ); -N(Ci-C 6 alkylene-0-Ci- C 6 alkyl) 2 (e.g. -N(CH 2 CH 2 OMe) 2 ); -N(Ci-C 6 alkyl)(Ci-C 6 alkylene-0-Ci-C 6 alkyl) (e.g.
  • R M is -L S -R E where L s is Ci-C 6 alkylene (e.g., -CH 2 - -C(CH 3 ) 2 -, -C(CH 3 ) 2 -CH 2 -) and R E is -0-R s , -C(0)OR s , - N(R s )C(0)ORs', or -P(0)(OR s ) 2 .
  • L s is Ci-C 6 alkylene (e.g., -CH 2 - -C(CH 3 ) 2 -, -C(CH 3 ) 2 -CH 2 -) and R E is -0-R s , -C(0)OR s , - N(R s )C(0)ORs', or -P(0)(OR s ) 2 .
  • R M is -Ci-C 6 alkylene-0-R s (e.g., -C(CH 3 ) 2 -CH 2 - OMe); -Ci-C 6 alkylene-C(0)OR s (e.g., -C(CH 3 ) 2 -C(0)OMe); -Ci-C 6 alkylene-N(R s )C(0)OR s ' (e.g., -C(CH 3 ) 2 -CH 2 -NHC(0)OCH 3 ); or -C 1 -C 6 alkylene-P(0)(OR s ) 2 (e.g., -CH 2 -P(0)(OEt) 2 ).
  • R M is -Ci-C 6 alkylene-0-R s (e.g., -C(CH 3 ) 2 -CH 2 - OMe); -Ci-C 6 alkylene-C(0)OR s (e.g., -C(CH 3 ) 2
  • R M is C 3 -C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, - C(0)OR s , or -N(R S R S ').
  • R M is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l- methylcycloprop-l-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1 - dioxidothiomorpholin-4-yl, 4-methylpiperazin-l-yl, 4-methoxycarbonylpiperazin-l -yl, pyrrolidin-1- yl, piperidin-l -yl, 4-methylpiperidin-l-yl, 3,5-dimethylpiperidin-l -yl, 4,4-difluoropiperidin-l-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl).
  • cycloalkyl e.g., cyclopropyl, 2,2-dichloro-
  • R M is Ci-C 6 alkyl which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF 3 ).
  • D is C 5 -C 6 carbocycle, 5- to 6-membered heterocycle or 6- to 12-membered bicycle and is substituted with J and optionally substituted with one or more R A
  • J is C 3 - Cecarbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R A .
  • J is substituted with a C 3 -C 6 carbocycle or 3- to 6- membered heterocycle, wherein said C 3 -C 6 carbocycle or 3- to 6-membered heterocycle is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or - N(R S R S '), and J can also be optionally substituted with one or more R A .
  • substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
  • D is C 5 - C 6 carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R A
  • J is C 3 -C 6 carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R A
  • J is at least substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 - C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or -N(
  • D is C 5 -C 6 carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R A
  • J is 6- to 12-membered bicycle (e.g., a 7- to 12-membered fused, bridged or spiro bicycle comprising a nitrogen ring atom through which J is covalently attached to D) and is optionally substituted with one or more R A .
  • D is phenyl and is substituted with J and optionally substituted with one or more R A
  • J is C 3 -C 6 carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R A
  • J is at least substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 ha C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or -
  • D is , wherein each R N is independently selected from R D and preferably is hydrogen or halogen, and J is C 3 -C 6 carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR S or -
  • D is , wherein each R N is independently selected from R D and preferably is hydrogen or halogen, and J is C 3 -C 6 carbocycle or 3- to 6-membered heterocycle and is substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or -
  • N(R S R S '), and J can also be optionally substituted with one or more R A .
  • D is and J is C 3 -C 6 carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R A
  • J is at least substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or -N(R s R s ').
  • X 3 is N and is directly linked to -L 3 -D
  • RA or R F is optionally substituted with one or more RA or R F .
  • Non-limiting examples of X are described hereinabove.
  • Li and L 2 are preferably independently bond or Ci-C 6 alkylene
  • L 3 is preferably selected from bond, Ci-C 6 alkylene or -C(O)-
  • L u L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • L u L 2 and L 3 are each independently bond or Ci-C 6 alkylene (e.g., - CH 2 - or -CH 2 CH 2 -), and are each independently optionally substituted with one or more RL.
  • L L 2 and L 3 are bond.
  • R 2 and R 5 taken together with the atoms to which they are attached, preferably form a 5- to 6-
  • membered heterocycle or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more RA.
  • R 9 and Ri 2 taken together with the atoms to which they are attached, preferably form a 5- to
  • 6-membered heterocycle or 6- to 12-membered bicycle e.g., which is optionally substituted with one or more R A .
  • -T-RD' can be, without limitation, independently selected at each occurrence from -C(O)- L Y '-, -C(0)0-L Y '-R D ', -C(0)-L Y '-N(RB)C(0)-L S "-R D ' , -C(0)-L Y '-N(R B )C(0)0-L S "-R D ' , - N(RB)C(0)-L Y '-N(RB)C(0)-L S "-R D ', -N(RB)C(0)-L Y '— N(RB)C(0)0-L S "-R d ', or -N(R B )C(0)- L Y '— N(R B )-L S "-RD', wherei ' is each independently L S ' and, preferably, is each independently Ci-C 6 alkylene (e.g., -CH 2 - or ) and optionally substituted with one or more substituent
  • -T-R D ' is independently selected at each occurrence from -C(0)-L Y '- M'-L S "-R D ' or -N(RB)C(0)-L Y '-M'-L S "-R d ' . More preferably, -T-R D ' is independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)-L S "-R D ' or -C(0)-L Y '-N(R B )C(0)0-L S "-R D ' .
  • -T-RD' is independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)- R D ' or -C(0)- '-N(R B )C(0)0-R D ' , wherein L Y ' preferably is each independently Ci-C 6 alkylene
  • RNB and Rc' are preferably hydrogen, and R D ' preferably is independently selected at each occurrence from R E . More preferably, R D ' is independently selected at each occurrence from Ci- Cealkyl, C2-Cealkenyl or C2-Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C 3 -C 6 carbocycle or 3- to 6-membered heterocycle; or C 3 -C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C
  • R A preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C2-C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-Ceal
  • R A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-Cealkyl, C2-Cealkenyl or C2-Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C 3 -C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-Cealkenyl or
  • R A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.
  • L s , Ls' and L s preferably are each independently selected at each occurrence from bond; or Ci-C 6 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene.
  • a and B can be the same or different.
  • Li and L 2 can be the same or different.
  • a and B are each independently phenyl, and are each independently optionally substituted with one or more R A ;
  • D is phenyl, and is optionally substituted with one or more R A , or is substituted with J and optionally substituted with one or more R A , wherein J is C 3 -C 6 carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R A .
  • J is substituted with a C 3 -C 6 carbocycle or 3- to 6- membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 - C 6 haloalkynyl, C(0)OR s or -N(R S R S '), J can also be optionally substituted with one or more R A .
  • substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6
  • D is or , wherein R M and R N are as defined above.
  • D is wherein J and R N are as defined above.
  • Li and L 2 are each independently bond or Ci-C 6 alkylene, and L 3 is bond, Ci-C 6 alkylene or -C(O)-, and L u L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • Li, L 2 , and L 3 are bond.
  • - T-R D ' is independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)-L S "-R D ' or -C(O)- L Y '-N(R B )C(0)0-L S "-R D ' , wherein L Y ' is Ci-C 6 alkylene (e.g., -CH 2 -) and optionally substituted with one or more substituents selected from R L , and L s " preferably is bond.
  • -T-R D ' can also be, without limitation, selected from -C(0)-L Y '-L S "-RD', -C(0)-L y '-0-L S "-R D ', -C(0)-L Y '-N(R B )- L S "-R D ', or -C(0)-L Y '-N(R B )S "-R D ' .
  • R 2 and R 5 taken together with the atoms
  • a and B are each independently phenyl (e.g., and are each independently optionally substituted with one or more R A (preferably, A
  • X 3 is N and is directly linked to -L 3 -D, and X is optionally substituted with one or more RA or R F .
  • D is phenyl, and is substituted with J and optionally substituted with one or more R A .
  • J is C 3 - C 6 carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle or 13- to 15-membered carbocycle/heterocycle, and J is optionally substituted with one or more R A .
  • J is substituted with a C 3 -C 6 carbocycle, 3- to 6-membered heterocycle, 6- to 12- membered bicycle or 7- to 12-membered carbocycle/heterocycle, which is independently optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 - Cgalkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, -C(0)OR S or -N(R S R S '), or (2) trimethylsilyl, -0-R S , -S-R or -C 0 R and J can also be optionally substituted with one or more substituents selected from (1) halogen,
  • R A Preferably, D is in J is as defined above, and each R N is independently selected from R D and preferably is hydrogen or halo such as F.
  • Li and L 2 are each independently bond or Ci-C 6 alkylene, and L 3 is bond, Ci-C 6 alkylene or -C(O)-, and L u L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • Li, L 2 , and L 3 are bond.
  • - T-R D ' is independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)-L s "-R D ' or -C(O)- L Y '-N(R B )C(0)0-L s "-R D ', wherein L Y ' is Ci-C 6 alkylene (e.g., -CH 2 -) and optionally substituted with one or more substituents selected from R L , and L s " preferably is bond.
  • -T-R D ' can also be, without limitation, selected from -C(0)-L Y '-L s "-R D ', -C(0)-L Y '-0-L s "-R D ', -C(0)-L Y '-N(R B )- L S "-R D ', or -C(0)-L Y '-N(R B )S(0) 2 -L s "-R D '.
  • R 2 and R 5 taken together with the atoms to which
  • 6-membered heterocyclic ring e.g., or 6- to 12-
  • membered bicycle e.g., which is optionally substituted with one or more R A ; and R 9 and
  • Ri 2 taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (e.g., which is optionally substituted with one or more R A .
  • the present invention features compounds of Formula I B and pharmaceutically acceptable salts thereof:
  • R c ' is each independently selected from R c ;
  • R D ' is each independently selected from R D ;
  • R 2 and R 5 taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more R A ;
  • R 9 and R 12 taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more R A ;
  • A, B, D, X, Li, L 2 , L 3 , T, R A , Rc, and R D are as described above in Formula I.
  • a and B preferably are independently selected from 8- to 12-membered
  • bicycles such as or where Zi is independently selected at each occurrence from O, S, NH or CH 2 , Z 2 is independently selected at each occurrence from N or CH, Z 3 is independently selected at each occurrence from N or CH, Z 4 is independently selected at each occurrence from O, S, NH or CH 2 , and Wi, W 2 , W 3 , W 4 , W 5 and W 6 are each independently selected at each occurrence from CH or N.
  • a and B are each independently optionally substituted with one or more R A . More preferably, A is selected from is
  • B is selected from or and is optionally substituted with one or more R A , where Zi, Z 2 , Z 3 , Z 4 , Wi, W 2 ,
  • W 3 , W 4 , W 5 , W 6 are as defined above.
  • Z 3 is N and Z 4 is NH.
  • A can be
  • a and B are independently optionally substituted with one or more R A .
  • A is and A and B are substituted with one or more halogen, such as F or CI.
  • halogen such as F or CI.
  • the compounds of Formula I B can have significantly improved pharmacokinetic properties as well as improved inhibitory activity against certain HCV genotype la mutants, as compared to the same compounds but with unsubstituted benzimidazole.
  • D preferably is selected from C 5 -C 6 carbocycle, 5- to 6-membered heterocycle, or 6- to 12- membered bicycles, and is optionally substituted with one or more R A .
  • D can also be preferably selected from Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, and is optionally substituted with one or more substituents selected from R L .
  • D is C 5 -C 6 carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered bicycles, and is substituted with one or more R M , where R M is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L S -R E .
  • R M is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L S -R E .
  • D is phenyl, and is optionally substituted with one or more R A . More preferably, D is phenyl, and is substituted with one or more R wherein R is as defined above. Highly preferably, D is
  • each R N is independently selected from R D and preferably is hydrogen.
  • One or more R N can also preferably be halo such as F.
  • D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or more R A . More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or
  • D is , wherein R M is as defined above, and each R N is independently selected from R D and preferably is hydrogen.
  • R N can also preferably be halo such as F.
  • D is also preferably indanyl, 4,5,6,7- tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl, and is optionally substituted with one or more R A .
  • D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more R M .
  • D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more R M .
  • D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more R M .
  • R M is substituted with one or more R M .
  • R M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C 3 -C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C 2
  • R M is halogen, hydroxy, mercapto, amino, carboxy; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 - Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.
  • R M is Ci-C 6 alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.
  • R M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or R M is -L S -R E , wherein L s is a bond or Ci-C 6 alkylene, and R E is - N(R S R S '), -O-Rs, -C(0)R s , -C(0)OR s , -C(0)N(R s R s '), -N(R s )C(0)R s ', -N(R s )C(0)OR s ', - N(R s )S0 2 R s ', -S0 2 R s , -SRs, or -P(0)(OR s ) 2 , wherein R s and R s ' can be, for example, each independently selected at each occurrence from (1) hydrogen or (2) Ci-C 6 al
  • R M is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or Ci-C 6 alkyl (e.g., methyl, isopropyl, tert-butyl), C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy.
  • halogen e.g., fluoro, chloro, bromo, iodo
  • hydroxy, mercapto, amino, carboxy or Ci-C 6 alkyl (e.g., methyl, isopropyl, tert-butyl), C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituent
  • R M is CF 3 , - C(CF 3 ) 2 -OH, -C(CH 3 ) 2 -CN, -C(CH 3 ) 2 -CH 2 OH, or -C(CH 3 ) 2 -CH 2 NH 2 .
  • R M is -L s - R E where L s is a bond and R E is -N(R S R S ), -0-R s , -N(R s )C(0)OR s ', -N(R s )S0 2 R s ', -S0 2 R s , or - SR S .
  • R E is -N(Ci-C 6 alkyl) 2 (e.g., -NMe 2 ); -N(Ci-C 6 alkylene-0-Ci- C 6 alkyl) 2 (e.g. -N(CH 2 CH 2 OMe) 2 ); -N(Ci-C 6 alkyl)(Ci-C 6 alkylene-0-Ci-C 6 alkyl) (e.g.
  • R M is -L S -R E where Ls is Ci-Cealkylene (e.g., -CH 2 - -C(CH 3 ) 2 -, -C(CH 3 ) 2 -CH 2 -) and R E is -O-Rs, -C(0)OR s , - N(R s )C(0)OR s ', or -P(0)(OR s ) 2 .
  • Ls is Ci-Cealkylene (e.g., -CH 2 - -C(CH 3 ) 2 -, -C(CH 3 ) 2 -CH 2 -) and R E is -O-Rs, -C(0)OR s , - N(R s )C(0)OR s ', or -P(0)(OR s ) 2 .
  • R M is -Ci-C 6 alkylene-0-R s (e.g., -C(CH 3 ) 2 -CH 2 - OMe); -Ci-C 6 alkylene-C(0)OR s (e.g., -C(CH 3 ) 2 -C(0)OMe); -Ci-C 6 alkylene-N(R s )C(0)ORs' (e.g., -C(CH 3 )2-CH 2 -NHC(0)OCH 3 ); or -C 1 -C 6 alkylene-P(0)(OR s ) 2 (e.g., -CH 2 -P(0)(OEt) 2 ).
  • R M is -Ci-C 6 alkylene-0-R s (e.g., -C(CH 3 ) 2 -CH 2 - OMe); -Ci-C 6 alkylene-C(0)OR s (e.g., -C(CH 3 ) 2 -C(0)
  • R M is C 3 -C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, - C(0)OR s , or -N(R S R S ').
  • R M is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l- methylcycloprop-l-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1 - dioxidothiomo holin-4-yl, 4-methylpiperazin- 1 -yl, 4-methoxy carbonylpiperazin- 1 -yl, pyrrolidin- 1 - yl, piperidin-l -yl, 4-methylpiperidin-l-yl, 3,5-dimethylpiperidin-l -yl, 4,4-difluoropiperidin-l-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl).
  • cycloalkyl e.g., cyclopropyl, 2,
  • R M is Ci-C 6 alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF 3 ).
  • D is Cs-Cecarbocycle, 5- to 6-membered heterocycle or 6- to 12-membered bicycle and is substituted with J and optionally substituted with one or more R A
  • J is C 3 - Cecarbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R A .
  • J is substituted with a C 3 -C 6 carbocycle or 3- to 6- membered heterocycle, wherein said C 3 -C 6 carbocycle or 3- to 6-membered heterocycle is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or - N(R S R S '), and J can also be optionally substituted with one or more R A .
  • substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
  • D is C 5 - C 6 carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R A
  • J is C 3 -Cecarbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R A
  • J is at least substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 - C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or -N
  • D is C 5 -C 6 carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R A
  • J is 6- to 12-membered bicycle (e.g., a 7- to 12-membered fused, bridged or spiro bicycle comprising a nitrogen ring atom through which J is covalently attached to D) and is optionally substituted with one or more R A .
  • D is phenyl and is substituted with J and optionally substituted with one or more R A
  • J is C 3 -C 6 carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R A
  • J is at least substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 ha C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or -
  • D is , wherein each R N is independently selected from R D and preferably is hydrogen or halogen, and J is C 3 -C 6 carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR S or -
  • D is , wherein each R N is independently selected from R D and preferably is hydrogen or halogen, and J is C 3 -C 6 carbocycle or 3- to 6-membered heterocycle and is substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or -
  • N(R S R S '), and J can also be optionally substituted with one or more R A .
  • D is and J is C 3 -C 6 carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R A
  • J is at least substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Cealkyl, C 2 -Cealkenyl, C 2 -C 6 alkynyl, Ci-Cehaloalkyl, C 2 -Cehaloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or -N(R s R s ').
  • X preferably is C 5 -C 6 carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered
  • X 3 is N and is directly linked to -L 3 -D
  • RA or R F is optionally substituted with one or more RA or R F .
  • Non-limiting examples of X are described hereinabove.
  • Li and L 2 are preferably independently bond or Ci-C 6 alkylene
  • L 3 is preferably selected from bond, Ci-C 6 alkylene or -C(O)-
  • L u L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • L u L 2 and L 3 are each independently bond or Ci-C 6 alkylene (e.g., - CH 2 - or -CH 2 CH 2 -), and are each independently optionally substituted with one or more R L .
  • L L 2 and L 3 are bond.
  • R 2 and R 5 taken together with the atoms to which they are attached, preferably form a 5- to 6-
  • R9 and Ri 2 taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more RA.
  • -T-R D ' can be, without limitation, independently selected at each occurrence from -C(O)- L Y '-R D ', -C(0)0-L Y '-R D ', -C(0)-L Y '-N(RB)C(0)-L S "-R D ', -C(0)-L Y '-N(R B )C(0)0-L S "-R D ', - N(RB)C(0)-L Y '-N(RB)C(0)-L S "-R D ', -N(RB)C(0)-L Y '— N(RB)C(0)0-L S "-R d ', or -N(R B )C(0)- L Y '— (R B )-L S "-R D ', wherei ' is each independently L S ' and, preferably, is each independently
  • Ci-C 6 alkylene e.g., -CH 2 - or
  • -T-R D ' is independently selected at each occurrence from -C(0)-L Y '- M'-L S "-R D ' or -N(RB)C(0)-L Y '-M'-L S "-R d ' .
  • -T-R D ' is independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)-L S "-R D ' or -C(0)-L Y '-N(R B )C(0)0-L S "-R D ' .
  • -T-R D ' is independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)- R D ' or -C(0)- '-N(R B )C(0)0-R D ' , wherein L Y ' preferably is each independently Ci-C 6 alkylene
  • R C ' is preferably hydrogen, and R D ' preferably is independently selected at each occurrence from R E . More preferably, R D ' is independently selected at each occurrence from Ci-C 6 alkyl, C 2 - Cealkenyl or C 2 -Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C 3 -C 6 carbocycle or 3- to 6-membered heterocycle; or C3-C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,
  • R A preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C2-C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C 3 -C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-Ceal
  • R A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C 3 -C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-
  • R A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.
  • L s , L s ' and L s " preferably are each independently selected at each occurrence from bond; or Ci-C 6 alkylene, C 2 -C 6 alkenylene or C2-C 6 alkynylene.
  • a and B can be the same or different.
  • Li and L 2 can be the same or different.
  • a nd is
  • J is substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR S or - '), and J ca be optionally substituted with one or more R A .
  • D is
  • J and R N are as defined above.
  • Zi is independently selected at each occurrence from O, S, NH or CH 2 ; and Z 2 is independently selected at each occurrence from N and A and B are substituted with and/or B are halo-substituted benzimidazole (e.g., A is and B is ), the compounds of this embodiment can have significantly improved pharmacokinetic properties as well as improved inhibitory activity against certain HCV genotype la mutants, as compared to the same compounds but with unsubstituted benzimidazole.
  • Li and L 2 are each independently bond or Ci-Cealkylene, and L 3 is bond, Ci- C 6 alkylene or -C(O)-, and L L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • L L 2 , and L 3 are bond.
  • -T-R D ' is independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)-L s "-R D ' or -C(0)-L Y '-N(R B )C(0)0-L s "-R D ', wherein L Y ' is C Cealkylene (e.g., -CH 2 -) and optionally substituted with one or more substituents selected from R L , and L s " preferably is bond.
  • -T-R D ' can also be, without limitation, selected from -C(0)-L Y '-L s "- R D ', -C(0)-L Y '-0-L S "-R D ', -C(0)-L Y '-N(R B )-L S "-R d ', or -C(0)-L Y '-N(R B )S(0) 2 -L S "-R D '.
  • A is and optionally substituted
  • R A e.g., halogen
  • B is and is optionally substituted with one or more R A (e.g., halogen)
  • D is C 5 -C 6 carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more R A , or is substituted with J and optionally substituted with one or more R A , wherein J is C 3 -C 6 carbocycle, 3- to 6-membered heterocycle or 6- to 12- membered bicycle and is optionally substituted with one or more R A .
  • J is substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci- C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR S or -N(R S R S '), and J can also be
  • D is or , wherein R M
  • a and/or B are halo-substituted benzimidazole (e.g., A is
  • the compounds of this embodiment can have significantly improved pharmacokinetic properties as well as improved inhibitory activity against certain HCV genotype la mutants, as compared to the same compounds but with unsubstituted benzimidazole.
  • Li and L 2 are each independently bond or Ci-C 6 alkylene, and L 3 is bond, Ci-C 6 alkylene or -C(O)-, and L L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • Li, L 2 , and L 3 are bond.
  • -T-R D ' is independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)-L s "-R D ' or -C(0)-LY'-N(R B )C(0)0-LS"-RD', wherein L Y ' is Ci-C 6 alkylene (e.g., -CH 2 -) and optionally substituted with one or more substituents selected from R L , and L S " preferably is bond.
  • -T-R D ' can also be, without limitation, selected from -C(0)-L Y '-L S "-R D ' , -C(0)-L Y '-0-L S "-R D ' , -C(0)-L Y '- N(R B )-L S "-R D ' , or -C(0)-L Y '-N(RB)S(0) 2 -L S "-R D ' .
  • R 2 and R 5 taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or 6- to 12-membered
  • heterocycle or 6- to 12-membered bicycle e.g., which is optionally substituted with one or more RA. More preferably, R2 and R5, taken together with the atoms to which
  • A is and optionally substituted ferably, A is substiututed with at least one halogen such as F); B is
  • X is N and is directly linked to -
  • L 3 -D, and X is optionally substituted with one or more R A or R F .
  • D is phenyl, and is substituted with J and optionally substituted with one or more R A .
  • J is C3-C 6 carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle or 13- to 15-membered carbocycle/heterocycle, and J is optionally substituted with one or more R A .
  • J is substituted with a C 3 -C 6 carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle or 7- to 12-membered carbocycle/heterocycle, which is independently optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 - C 6 haloalkenyl, C 2 -C 6 haloalkynyl, -C(0)OR s or -N(R S R S '), or (2) trimethylsilyl, -0-R s , -S-R s or - C(0)R s ; and J can also be optionally substituted with one or
  • Li and L 2 are each independently bond or Ci- C 6 alkylene, and L 3 is bond, Ci-C 6 alkylene or -C(O)-, and L L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • L L 2 , and L 3 are bond.
  • -T-R D ' is independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)-L S "-R D ' or -C(0)-L Y '- N(R B )C(0)0-L S "-R D ' , wherein L Y ' is Ci-C 6 alkylene (e.g., -CH 2 -) and optionally substituted with one or more substituents selected from R L , and L S " preferably is bond.
  • -T-RD' can also be, without limitation, selected from -C(0)-L Y '-L S "-R D ' , -C(0)-L Y '-0-L S "-R D ', -C(0)-L Y '-N(R B )-L S "- R D ', or -C(0)-L Y '-N(R B )S(0) 2 -L S "-RD' .
  • R 2 and R 5 taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,
  • R9 and Ri 2 taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or
  • 6- to 12-membered bicycle e.g., is optionally substituted with one or m e preferably, R 2 and R 5 , taken together with the atoms to which they are attached,
  • the present invention further features compounds of Formula Ic and pharmaceutically acceptable salts thereof.
  • R C ' is each independently selected from R C ;
  • R D ' is each independently selected from R D ;
  • R 2 and R 5 taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more RA;
  • R 9 and R12 taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more R A ;
  • A, B, D, X, Li, L 2 , L 3 , T, R A , RB, RC, and R D are as described above in Formula I.
  • A preferably is C 5 -C 6 carbocycle or 5- to 6-membered heterocycle, and is optionally substituted with one or more R A ; and B preferably is 8- to 12-membered bicycle (such as or and is optionally substituted with one or more
  • Zi is O, S, NH or CH 2 ;
  • Z 2 is N or CH;
  • Z 3 is N or CH;
  • Z 4 is O, S, NH or CH 2 ;
  • Wi, W 2 , W 3 , W 4 , W 5 and W6 are each independently selected from CH or N.
  • A is phenyl (e.g., ), and is optionally substituted with one or
  • RA is and is optionally substituted with one or more R A , where Zi, Z 2 , Z 3 , Z 4 , Wi, W 2 , W 3 , W 4 , W 5 , W 6 are as defined above.
  • Z 3 is N and is optionally substituted with one or more R A i
  • A is 3 ⁇ 4 ) or 5- to 6-
  • B is selected from C 5 -C 6 carbocycle or 5- to 6-membered heterocycle.
  • a and B are independently optionally substituted with one or more R A .
  • D preferably is selected from C 5 -C 6 carbocycle, 5- to 6-membered heterocycle, or 6- to 12- membered bicycles, and is optionally substituted with one or more R A .
  • D can also be preferably selected from Ci-C 6 alkyl, C 2 -Cealkenyl or C 2 -C 6 alkynyl, and is optionally substituted with one or more substituents selected from R L .
  • D is C 5 -C 6 carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered bicycles, and is substituted with one or more R M , where R M is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L S -RE.
  • D is phenyl, and is optionally substituted with one or more R A . More preferably, D is phenyl, and is substituted with one or more R M , wherein R M is as defined above. Highly preferably, D is
  • each R N is independently selected from R D and preferably is hydrogen.
  • One or more R N can also preferably be halo such as F.
  • D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or more R A . More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or
  • D is , or , wherein R M is as defined above, and each R N is independently selected from R D and preferably is hydrogen.
  • R N can also preferably be halo such as F.
  • D is also preferably indanyl, 4,5,6,7- tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl, and is optionally substituted with one or more R A .
  • D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l ,3]dioxol-5-yl, and is substituted with one or more R M .
  • D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l ,3]dioxol-5-yl, and is substituted with one or more R M .
  • D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l ,3]dioxol-5-yl, and is substituted with one or more R M .
  • D is indanyl, 4,5,6,
  • R M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C 3 -C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano; or C 3 -C 6 carbocycle or 3-
  • R M is halogen, hydroxy, mercapto, amino, carboxy; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 - Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.
  • R M is Ci-C 6 alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.
  • R M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or R M is -L S -R E , wherein L s is a bond or Ci-C 6 alkylene, and R E is - N(R S R S '), -O-Rs, -C(0)R s , -C(0)OR s , -C(0)N(R s R s '), -N(R s )C(0)R s ', -N(R s )C(0)OR s ', - N(R s )S0 2 R s ', -S0 2 R s , -SRs, or -P(0)(OR s ) 2 , wherein R s and R s ' can be, for example, each independently selected at each occurrence from (1) hydrogen or (2) Ci-C 6 al
  • R M is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or Ci-C 6 alkyl (e.g., methyl, isopropyl, tert-butyl), C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy.
  • halogen e.g., fluoro, chloro, bromo, iodo
  • hydroxy, mercapto, amino, carboxy or Ci-C 6 alkyl (e.g., methyl, isopropyl, tert-butyl), C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituent
  • R M is CF 3 , - C(CF 3 ) 2 -OH, -C(CH 3 ) 2 -CN, -C(CH 3 ) 2 -CH 2 OH, or -C(CH 3 ) 2 -CH 2 NH 2 .
  • R M is -L s - R E where L s is a bond and R E is -N(R S R S ), -0-R s , -N(R s )C(0)OR s ', -N(R s )S0 2 R s ', -S0 2 R s , or - SR S .
  • R E is -N(Ci-C 6 alkyl) 2 (e.g., -NMe 2 ); -N(Ci-C 6 alkylene-0-Ci- C 6 alkyl) 2 (e.g. -N(CH 2 CH 2 OMe) 2 ); -N(Ci-C 6 alkyl)(Ci-C 6 alkylene-0-Ci-C 6 alkyl) (e.g.
  • R M is -L S -R E where L s is C C 6 alkylene (e.g., -CH 2 - -C(CH 3 ) 2 -, -C(CH 3 ) 2 -CH 2 -) and R E is -0-R s , -C(0)OR s , - N(R s )C(0)OR s ', or -P(0)(OR s ) 2 .
  • L s is C C 6 alkylene (e.g., -CH 2 - -C(CH 3 ) 2 -, -C(CH 3 ) 2 -CH 2 -) and R E is -0-R s , -C(0)OR s , - N(R s )C(0)OR s ', or -P(0)(OR s ) 2 .
  • R M is -Ci-C 6 alkylene-0-R s (e.g., -C(CH 3 ) 2 -CH 2 - OMe); -Ci-C 6 alkylene-C(0)OR s (e.g., -C(CH 3 ) 2 -C(0)OMe); -Ci-C 6 alkylene-N(R s )C(0)OR s ' (e.g., -C(CH 3 ) 2 -CH 2 -NHC(0)OCH 3 ); or -C 1 -C 6 alkylene-P(0)(OR s ) 2 (e.g., -CH 2 -P(0)(OEt) 2 ).
  • R M is -Ci-C 6 alkylene-0-R s (e.g., -C(CH 3 ) 2 -CH 2 - OMe); -Ci-C 6 alkylene-C(0)OR s (e.g., -C(CH 3 ) 2
  • R M is C 3 -C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, - C(0)OR s , or -N(R S R S ').
  • R M is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l- methylcycloprop-l-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1 - dioxidothiomo holin-4-yl, 4-methylpiperazin- 1 -yl, 4-methoxy carbonylpiperazin- 1 -yl, pyrrolidin- 1 - yl, piperidin-l -yl, 4-methylpiperidin-l-yl, 3,5-dimethylpiperidin-l -yl, 4,4-difluoropiperidin-l-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl).
  • cycloalkyl e.g., cyclopropyl, 2,
  • R M is Ci-C 6 alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF 3 ).
  • D is C 5 -C 6 carbocycle, 5- to 6-membered heterocycle or 6- to 12-membered bicycle and is substituted with J and optionally substituted with one or more R A
  • J is C 3 - Cecarbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R A .
  • J is substituted with a C 3 -C 6 carbocycle or 3- to 6- membered heterocycle, wherein said C 3 -C 6 carbocycle or 3- to 6-membered heterocycle is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Cealkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or - N(R S R S '), and J can also be optionally substituted with one or more R A .
  • substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
  • D is C 5 - C 6 carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R A
  • J is C 3 -Cecarbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R A
  • J is at least substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 - C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or -N
  • D is C 5 -C 6 carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R A
  • J is 6- to 12-membered bicycle (e.g., a 7- to 12-membered fused, bridged or spiro bicycle comprising a nitrogen ring atom through which J is covalently attached to D) and is optionally substituted with one or more R A .
  • D is phenyl and is substituted with J and optionally substituted with one or more R A
  • J is C 3 -C 6 carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA
  • J is at least substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 ha C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR S or -
  • D is , wherein each R N is independently selected from R D and preferably is hydrogen or halogen, and J is C 3 -C 6 carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR S or -
  • D is , wherein each R N is independently selected from R D and preferably is hydrogen or halogen, and J is C 3 -C 6 carbocycle or 3- to 6-membered heterocycle and is substituted with a C 3 -Cecarbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or -
  • N(R S R S '), and J can also be optionally substituted with one or more R A .
  • D is and J is C 3 -C 6 carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C 3 -Cecarbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Q-Cealkyl, C2-Cealkenyl, C2-C 6 alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl, C2-Cehaloalkynyl, C(0)OR s or -N(R s R s ').
  • X preferably is C 5 -C 6 carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered
  • X 3 is N and is directly linked to -L 3 -D
  • RA or R F is optionally substituted with one or more RA or R F .
  • Non-limiting examples of X are described hereinabove.
  • Li and L 2 are preferably independently bond or Ci-C 6 alkylene
  • L 3 is preferably selected from bond, Ci-C 6 alkylene or -C(O)-
  • Li, L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • Li, L 2 and L 3 are each independently bond or Ci-C 6 alkylene (e.g., - CH 2 - or -CH 2 CH 2 -), and are each independently optionally substituted with one or more R L .
  • Li, L 2 and L 3 are bond.
  • Li and L 2 can be the same or different.
  • R 2 and R 5 taken together with the atoms to which they are attached, preferably form a 5- to 6-
  • R9 and R12 taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more RA.
  • -T-RD' can be, without limitation, independently selected at each occurrence from -C(O)- L Y '-R D ', -C(0)0-L Y '-R D ', -C(0)-L Y '-N(RB)C(0)-L S "-R D ', -C(0)-L Y '-N(R B )C(0)0-L S "-R D ', - N(RB)C(0)-L Y '-N(RB)C(0)-L S "-R D ', -N(R B )C(0)-L Y '— N(RB)C(0)0-LS"-R d ', or -N(R B )C(0)- L Y '— (R B )-L S "-R D ', wherei ' is each independently L S ' and, preferably, is each independently
  • Ci-C 6 alkylene e.g., -CH 2 - or
  • -T-R D ' is independently selected at each occurrence from -C(0)-L Y '- M'-L S "-R D ' or -N(R B )C(0)-L Y '-M'-L s "-R D ' .
  • -T-R D ' is independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)-L s "-R D ' or -C(0)-L Y '-N(R B )C(0)0-L s "-R D '.
  • -T-R D ' is independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)- R D ' or -C(0)- '-N(R B )C(0)0-RD', wherein L Y ' preferably is each independently Ci-Cealkylene
  • R N B and Rc' are preferably hydrogen, and R D ' preferably is independently selected at each occurrence from R E . More preferably, R D ' is independently selected at each occurrence from Ci- Cealkyl, C2-Cealkenyl or C2-Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C 3 -C 6 carbocycle or 3- to 6-membered heterocycle; or C 3 -C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,
  • R A preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C2-C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C 3 -C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-Ceal
  • R A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C 3 -C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-
  • R A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-Cealkyl, C2-Cealkenyl or C2-Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.
  • L s , L s ' and L s " preferably are each independently selected at each occurrence from bond; or Ci-C 6 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene.
  • D is C 5 -C6carbocycle or 5- to 6- membered heterocycle (e.g., phenyl), and is optionally substituted with one or more R A , or is substituted with J and optionally substituted with one or more R A , wherein J is C 3 -C 6 carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R A .
  • J is substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR S or - N(R S R S '), and J can also be optionally substituted with one or more R A .
  • D is
  • Li and L 2 are each independently bond or Ci-C 6 alkylene, and L 3 is bond, Ci-C 6 alkylene or -C(O)-, and L L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • L L 2 , and L 3 are bond.
  • -T- R D ' is independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)-L s "-R D ' or -C(O)- L Y '-N(R B )C(0)0-L s "-R D ', wherein L Y ' is Ci-C 6 alkylene (e.g., -CH 2 -) and optionally substituted with one or more substituents selected from R L , and L s " preferably is bond.
  • -T-R D ' can also be, without limitation, selected from -C(0)-L Y '-L s "-R D ', -C(0)-L Y '-0-L s "-R D ', -C(0)-L Y '-N(R B )- L S "-R D ', or -C(0)-L Y '-N(R B )S "-R D ' .
  • R 2 and R 5 taken together with the atoms
  • R9 and Rn taken together with the atoms to which they are attached, form which is optionally substituted with one or more R A .
  • B is and is optionally substituted with one or more R A (preferably, B is
  • X is wherein X 3 is N and is directly linked to -L 3 -D, and X is optionally substituted with one or more R A or R F .
  • D is phenyl, and is substituted with J and optionally substituted with one or more R A .
  • J is C 3 -C 6 carbocycle, 3- to 6- membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle or 13- to 15- membered carbocycle/heterocycle, and J is optionally substituted with one or more R A .
  • J is substituted with a C 3 -C 6 carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle or 7- to 12-membered carbocycle/heterocycle, which is independently optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C 2 -Cealkenyl, C2-C6alkynyl, d- Cehaloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, -C(0)OR s or -N(R S R S '), or (2) trimethylsilyl, -O- R s , -S-Rs or -C(0)R s ; and J can also be optionally substituted with one or more R A
  • Li and L 2 are each independently bond or Ci- C 6 alkylene, and L 3 is bond, Ci-C 6 alkylene or -C(O)-, and Li, L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • Li, L 2 , and L 3 are bond.
  • -T-R D ' is independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)-L S "-R D ' or -C(0)-L Y '- N(R B )C(0)0-L S "-R D ', wherein L Y ' is Ci-C 6 alkylene (e.g., -CH 2 -) and optionally substituted with one or more substituents selected from R L , and L S " preferably is bond.
  • -T-R D ' can also be, without limitation, selected from -C(0)-L Y '-L S "-R D ', -C(0)-L Y '-0-L S "-R D ', -C(0)-L Y '-N(R B )-L S "- R D ', or -C(0)-L Y '-N(R B )S(0) 2 -L S "-R D '.
  • R 2 and R 5 taken together with the atoms to which they are attached, or 6- to 12-
  • membered bicycle e.g., R A ; R9 and
  • ring e.g., or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more R A .
  • the present invention features compounds of Formula I D and pharmaceutically acceptable salts thereof.
  • Gi and G 2 are each independently selected from C 5 -C 6 carbocycle or 5- to 6-membered heterocycle, and are each independently optionally substituted with one or more R A ;
  • Rc' is each independently selected from R c ;
  • R D ' is each independently selected from R D ;
  • R 2 and R 5 taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more R A ;
  • R 9 and R12 taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more R A ;
  • A, B, D, X, Li, L 2 , L 3 , T, R A , R c , and R D are as described above in Formula I.
  • D preferably is selected from C 5 -C 6 carbocycle, 5- to 6-membered heterocycle, or 8- to 12- membered bicycles, and is optionally substituted with one or more RA.
  • D can also be preferably selected from Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, and is optionally substituted with one or more R L .
  • D is C 5 -C 6 carbocycle, 5- to 6-membered heterocycle, or 6- to 12- membered bicycles, and is substituted with one or more R M , where R M is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L S -R E .
  • R M is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L S -R E .
  • D is phenyl, and is optionally substituted with one or more R A . More preferably, D is phenyl, and is substituted with one or more
  • R M is as defined above. Highly preferably, D is or , wherein R M is as defined above, and each R N is independently selected from R D and preferably is hydrogen. One or more R N can also preferably be halo such as F.
  • D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or more R A . More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or
  • D is , wherein R M is as defined above, and each R N is independently selected from R D and preferably is hydrogen.
  • R N can also preferably be halo such as F.
  • D is also preferably indanyl, 4,5,6,7- tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl, and is optionally substituted with one or more RA.
  • D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l ,3]dioxol-5-yl, and is substituted with one or more R M .
  • D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l ,3]dioxol-5-yl, and is substituted with one or more R M .
  • D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l ,3]dioxol-5-yl, and is substituted with one or more R M .
  • D is indanyl, 4,5,6,
  • R M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C 3 -C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C 3 -C 6 carbocycle or 3-
  • R M is halogen, hydroxy, mercapto, amino, carboxy; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 - Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.
  • R M is Ci-C 6 alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.
  • R M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or R M is -L S -R E , wherein L s is a bond or Ci-C 6 alkylene, and R E is - N(R S R S '), -O-Rs, -C(0)R s , -C(0)OR s , -C(0)N(R s R s '), -N(R s )C(0)R s ', -N(R s )C(0)OR s ', - N(R s )S0 2 R s ', -S0 2 R s , -SRs, or -P(0)(OR s ) 2 , wherein R s and R s ' can be, for example, each independently selected at each occurrence from (1) hydrogen or (2) Ci-C 6 al
  • R M is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or Ci-C 6 alkyl (e.g., methyl, isopropyl, tert-butyl), C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy.
  • halogen e.g., fluoro, chloro, bromo, iodo
  • hydroxy, mercapto, amino, carboxy or Ci-C 6 alkyl (e.g., methyl, isopropyl, tert-butyl), C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituent
  • R M is CF 3 , - C(CF 3 ) 2 -OH, -C(CH 3 ) 2 -CN, -C(CH 3 ) 2 -CH 2 OH, or -C(CH 3 ) 2 -CH 2 NH 2 .
  • R M is -L s - R E where L s is a bond and R E is -N(R S R S ), -0-R s , -N(R s )C(0)OR s ', -N(R s )S0 2 R s ', -S0 2 R s , or - SR S .
  • R E is -N(Ci-C 6 alkyl) 2 (e.g., -NMe 2 ); -N(Ci-C 6 alkylene-0-Ci- C 6 alkyl) 2 (e.g. -N(CH 2 CH 2 OMe) 2 ); -N(Ci-C 6 alkyl)(Ci-C 6 alkylene-0-Ci-C 6 alkyl) (e.g.
  • R M is -L S -R E where L s is C C 6 alkylene (e.g., -CH 2 - -C(CH 3 ) 2 -, -C(CH 3 ) 2 -CH 2 -) and R E is -0-R s , -C(0)OR s , - N(R s )C(0)OR s ', or -P(0)(OR s ) 2 .
  • L s is C C 6 alkylene (e.g., -CH 2 - -C(CH 3 ) 2 -, -C(CH 3 ) 2 -CH 2 -) and R E is -0-R s , -C(0)OR s , - N(R s )C(0)OR s ', or -P(0)(OR s ) 2 .
  • R M is -Ci-C 6 alkylene-0-R s (e.g., -C(CH 3 ) 2 -CH 2 - OMe); -Ci-C 6 alkylene-C(0)OR s (e.g., -C(CH 3 ) 2 -C(0)OMe); -Ci-C 6 alkylene-N(R s )C(0)OR s ' (e.g., -C(CH 3 ) 2 -CH 2 -NHC(0)OCH 3 ); or -C 1 -C 6 alkylene-P(0)(OR s ) 2 (e.g., -CH 2 -P(0)(OEt) 2 ).
  • R M is -Ci-C 6 alkylene-0-R s (e.g., -C(CH 3 ) 2 -CH 2 - OMe); -Ci-C 6 alkylene-C(0)OR s (e.g., -C(CH 3 ) 2
  • R M is C 3 -C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, - C(0)OR s , or -N(R S R S ').
  • R M is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l- methylcycloprop-l-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1- dioxidothiomo holin-4-yl, 4-methylpiperazin- 1 -yl, 4-methoxy carbonylpiperazin- 1 -yl, pyrrolidin- 1 - yl, piperidin-l -yl, 4-methylpiperidin-l-yl, 3,5-dimethylpiperidin-l -yl, 4,4-difluoropiperidin-l-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl).
  • cycloalkyl e.g., cyclopropyl, 2,2-
  • R M is Ci-C 6 alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF 3 ).
  • D is C 5 -C 6 carbocycle, 5- to 6-membered heterocycle or 6- to 12-membered bicycle and is substituted with J and optionally substituted with one or more R A
  • J is C 3 - Cecarbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R A .
  • J is substituted with a C 3 -C 6 carbocycle or 3- to 6- membered heterocycle, wherein said C 3 -C 6 carbocycle or 3- to 6-membered heterocycle is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Cealkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or - N(R S R S '), and J can also be optionally substituted with one or more R A .
  • substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
  • D is C 5 - C 6 carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R A
  • J is C 3 -Cecarbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R A
  • J is at least substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 - C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or -N
  • D is C 5 -C 6 carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R A
  • J is 6- to 12-membered bicycle (e.g., a 7- to 12-membered fused, bridged or spiro bicycle comprising a nitrogen ring atom through which J is covalently attached to D) and is optionally substituted with one or more R A .
  • D is phenyl and is substituted with J and optionally substituted with one or more R A
  • J is C 3 -C 6 carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA
  • J is at least substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 ha C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR S or -
  • D is , wherein each R N is independently selected from R D and preferably is hydrogen or halogen, and J is C 3 -C 6 carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C 3 -C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR S or -
  • D is , wherein each R N is independently selected from R D and preferably is hydrogen or halogen, and J is C 3 -C 6 carbocycle or 3- to 6-membered heterocycle and is substituted with a C 3 -Cecarbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or -
  • N(R S R S '), and J can also be optionally substituted with one or more R A .
  • D is and J is C 3 -C 6 carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C 3 -Cecarbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Q-Cealkyl, C 2 -Cealkenyl, C 2 -C 6 alkynyl, Ci-Cehaloalkyl, C 2 -Cehaloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or -N(R s R s ').
  • X preferably is C 5 -C 6 carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered
  • X 3 is N and is directly linked to -L 3 -D
  • RA or R F is optionally substituted with one or more RA or R F .
  • Non-limiting examples of X are described hereinabove.
  • Li and L 2 are preferably independently bond or Ci-C 6 alkylene
  • L 3 is preferably selected from bond, Ci-C 6 alkylene or -C(O)-
  • Li, L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • Li, L 2 and L 3 are each independently bond or Ci-C 6 alkylene (e.g., - CH 2 - or -CH 2 CH 2 -), and are each independently optionally substituted with one or more R L .
  • Li, L 2 and L 3 are bond.
  • R 2 and R 5 taken together with the atoms to which they are attached, preferably form a 5- to 6-
  • membered heterocycle or 6- to 12-membered bicycle (e.g., which optionally substituted with one or more R A .
  • Rg and R 12 taken together with the atoms to which they are attached, preferably form a 5-
  • 6-membered heterocycle or 6- to 12-membered bicycle e.g.,
  • H are each independently selected from — N , N- , and are each independently optionally substituted with one or more
  • RA e.g., one or more chloro or bromo. More preferably, Gi is (including any tautomer thereof), and G 2 is ⁇ (including any tautomer thereof), and each Gi and G 2 is independently optionally substituted with one or more RA (e.g., one or more chloro or bromo).
  • -T-RD' can be, without limitation, independently selected at each occurrence from -C(O)- L Y '-, -C(0)0-L Y '-R D ', -C(0)-L Y '-N(RB)C(0)-L S "-R D ' , -C(0)-L Y '-N(R B )C(0)0-L S "-R D ' , - N(RB)C(0)-L Y '-N(RB)C(0)-L S "-R D ', -N(RB)C(0)-L Y '— N(RB)C(0)0-L S "-R d ', or -N(R B )C(0)- L Y '— N(R B )-L S "-R D ', wherei ' is each independently L S ' and, preferably, is each independently Ci-C 6 alkylene (e.g., -CH 2 - or ) and optionally substituted with one or more
  • -T-R D ' is independently selected at each occurrence from -C(0)-L Y '- M'-L S "-R D ' or -N(RB)C(0)-L Y '-M'-L S "-R d ' . More preferably, -T-R D ' is independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)-L S "-R D ' or -C(0)-L Y '-N(R B )C(0)0-L S "-R D ' .
  • -T-R D ' is independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)- R D ' or -C(0)- '-N(R B )C(0)0-R D ' , wherein L Y ' preferably is each independently Ci-C 6 alkylene
  • R c ' is preferably hydrogen, and R D ' preferably is independently selected at each occurrence from R E . More preferably, R D ' is independently selected at each occurrence from Ci-C 6 alkyl, C 2 - Cealkenyl or C2-Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C 3 -C 6 carbocycle or 3- to 6-membered heterocycle; or C 3 -C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano,
  • R A preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C2-C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C 3 -C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C Cealkyl, C2-Cealken
  • R A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C 3 -C 6 carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C Cealkyl, C 2
  • R A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.
  • L s , L s ' and L s " preferably are each independently selected at each occurrence from bond; or Ci-C 6 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene.
  • a and B can be the same or different.
  • Li and L 2 can be the same or different.
  • a and B are each independently phenyl, and are each independently optionally substituted with one or more R A ;
  • D is phenyl, and is independently optionally substituted with one or more R A , or is substituted with J and optionally substituted with one or more R A , wherein J is C 3 -C 6 carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R A .
  • J is substituted with a C 3 - C 6 carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci- C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C(0)OR s or -N(R S R S '), and J can also be optionally substituted with one or more R A ; and Gi is , and each Gi and G 2 is independently optionally substituted with one or more R A (e.g., one or more chloro or bromo).
  • substituents selected from halogen, hydroxy, mercapto, amino
  • D is or , wherein J and R N are as defined above.
  • Li and L 2 are each independently bond or Ci-Cealkylene, and L 3 is bond, Ci-Cealkylene or -C(O)-, and Li, L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • Li, L 2 , and L 3 are bond.
  • - T-R D ' is independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)-L S "-R D ' or -C(O)- L Y '-N(R B )C(0)0-L S "-R D ', wherein L Y ' is Ci-C 6 alkylene (e.g., -CH 2 -) and optionally substituted with one or more substituents selected from R L , and L s " preferably is bond.
  • -T-R D ' can also be, without limitation, selected from -C(0)-L Y '-L S "-R D ', -C(0)-L Y '-0-L S "-R D ', -C(0)-L Y '-N(R B )- L S "-R D ', or -C(0)-L Y '-N(R B )S "-R d '.
  • R 2 and R 5 taken together with the atoms
  • a and B are each independently phenyl (e.g., and are each independently optionally substituted with one or more R A (preferably, A
  • X 3 is N and is directly linked to -L 3 -D, and X is optionally substituted with one or more R A or R F .
  • D is phenyl, and is substituted with J and optionally substituted with one or more R A .
  • J is C 3 - C 6 carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle or 13- to 15-membered carbocycle/heterocycle, and J is optionally substituted with one or more R A .
  • J is substituted with a C 3 -C 6 carbocycle, 3- to 6-membered heterocycle, 6- to 12- membered bicycle or 7- to 12-membered carbocycle/heterocycle, which is independently optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 - Cgalkynyl, Ci-C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, -C(0)OR S or -N(R S R S '), or (2) trimethylsilyl, -0-R S , -S-R S or -C(0)R S ; and J can also be optionally substituted with one or more R A .
  • H independently selected from R D and preferably is hydrogen or halo such as F.
  • Gi is N
  • G 2 is and each Gi and G 2 is independently optionally substituted with one or more R A (e.g., one or more chloro or bromo).
  • Li and L 2 are each independently bond or Ci-Cealkylene
  • L 3 is bond, Ci-C 6 alkylene or -C(O)-
  • L L 2 , and L 3 are each independently optionally substituted with one or more R L .
  • Li, L 2 , and L 3 are bond.
  • -T-R D ' is independently selected at each occurrence from -C(0)-L Y '-N(R B )C(0)-L S "-R D ' or -C(0)-L Y '-N(R B )C(0)0-L S "-R D ', wherein L Y ' is Ci-C 6 alkylene (e.g., -CH 2 -) and optionally substituted with one or more substituents selected from R L , and L s " preferably is bond.
  • -T-R D ' can also be, without limitation, selected from -C(O)- L Y '-L S "-R D ', -C(0)-L Y '-0-L S "-R D ', -C(0)-L Y '-N(R B )-L S "-R D ', or -C(0)-L Y '-N(R B )S(0) 2 - L S "-R D '.
  • R 2 and R5 taken together with the atoms to which they are attached, form a 5-
  • 6-membered heterocyclic ring e.g., 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more R A ; R9 and Ri 2 , taken together with the atoms to
  • membered bicycle e.g., one or more R A .
  • the present invention features compounds having Formula I E and pharmaceutically acceptable salts thereof,
  • X is 4- to 8-membered heterocycle, and is optionally substituted with one or more R A ;
  • Li and L 2 are each independently selected from bond or Ci-Cealkylene which is independently optionally substituted at each occurrence with one or more halo, hydroxy, -0-Ci-C 6 alkyl, or -0-Ci-C 6 haloalkyl;
  • L 3 is bond or Ci-C 6 alkylene
  • a and B are each independently phenyl, pyridinyl, thiazolyl,
  • a and B are each independently optionally substituted with one or more R A .
  • D is C6-Ciocarbocycle or 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R M 5
  • Y is -T'-C(R 1 R 2 )N(R 5 )-T-R D ;
  • Z is -T'-C(R 8 R 9 )N(R 12 )-T-R D ;
  • Ri is hydrogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or 3- to 6-membered carbocycle or heterocycle, wherein each said 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, -0-Ci-C 6 alkyl or -0-Ci-C 6 haloalkyl;
  • R 2 and R 5 are each independently hydrogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or 3- to 6-membered carbocycle or heterocycle, wherein each said 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, -0-Ci-C 6 alkyl or -0-Ci-C 6 haloalkyl; or R 2 and R 5 , taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more R A (e.g., 1, 2, 3, or 4 R A );
  • R A e.g., 1, 2, 3, or 4 R A
  • R 8 is hydrogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or 3- to 6-membered carbocycle or heterocycle, wherein each said 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, -0-Ci-C 6 alkyl or -0-Ci-C 6 haloalkyl;
  • R 9 and Ri 2 are each independently hydrogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or 3- to 6- membered carbocycle or heterocycle, wherein each said 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from halogen, Ci-Cealkyl, Ci-Cehaloalkyl, -O-Ci-Cealkyl or -O-Ci- Cehaloalkyl; or Rg and R 12 , taken together with the atoms to which they are attached, form a 3- to 12-membered heterocycle which is optionally substituted with one or more RA (e.g., l, 2, 3, or 4 R A );
  • RA e.g., l, 2, 3, or 4 R A
  • T is independently selected at each occurrence from bond or -C(0)-L s '-;
  • T' is independently selected at each occurrence from bond, -C(0)N(R B )-, -N(R B )C(0)-, or
  • 3- to 12-membered heterocycle wherein said 3- to 12-membered heterocycle is independently optionally substituted at each occurrence with one or more R A ;
  • R D is each independently selected at each occurrence from hydrogen or R A ;
  • R A is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L S -R E ;
  • R B and R B ' are each independently selected at each occurrence from hydrogen; or Ci-C 6 alkyl which is independently optionally substituted at each occurrence with one or more substituents selected from halogen or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in R B or R B ' is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, Ci-C 6 alkyl, Ci-C 6 haloalkyl, - 0-Ci-C 6 alkyl, or -0-C C 6 haloalkyl;
  • R E is independently selected at each occurrence from -0-R s , -S-R s , -C(0)R s , -OC(0)R s , - C(0)OR s , -N(RsRs'), -S(0)R s , -S0 2 R s , -C(0)N(R s R s '), -N(R s )C(0)R s ', - N(Rs)C(0)N(R s 'Rs"), -N(R s )S0 2 R s ', -S0 2 N(R s R s '), -N(R s )S0 2 N(R s 'R s "), -N(R s )S0 2 R s 'R s "), -N(R s )S0 2 R s 'R s "), -N(R s )S0 2 R s '
  • N(Rs)S(0)N(R s 'Rs"), -OS(0)-R s , -OS(0) 2 -R s , -S(0) 2 OR s , -S(0)OR s , -OC(0)OR s , - N(R s )C(0)ORs', -OC(0)N(R s R s '), -N(R s )S(0)-R s ', -S(0)N(R s R s '), -C(0)N(R s )C(0)- R s ', or C(R s Rs'); or Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo
  • R L is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, -0-R s , -S-R s , -C(0)R s , -OC(0)R s , -C(0)OR s , -N(R S R S '), - S(0)R s , -S0 2 R s , -C(0)N(R s R s '), or -N(R s )C(0)R s '; or C 3 -Ci 2 carbocycle or 3- to 12- membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Cealkyl, C2-C6al
  • R s ' and R s " are each independently selected at each occurrence from hydrogen; Q- Cealkyl, C2-Cealkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, -0-Ci-C 6 alkyl, -0-Ci-C 6 haloalkyl, or 3- to 12-membered carbocycle or heterocycle; or 3- to 12-membered carbocycle or heterocycle; wherein each 3- to 12- membered carbocycle or heterocycle in R s , R s ' or R s " is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,
  • G 2 wherein G 2 is a C 3 -Ci 2 carbocycle or 3- to 12-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more RG2, and each R G2 is independently selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C 6 alkyl, C 2 - Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl, C2-C6haloalkynyl, -O- R s , -C(0)OR s , -C(0)R s , -N(R S R S '), or -L 4 -G 3 ; L 4 is a bond, Ci-Cealkylene, C 2 -C 6 alkenylene, C2-C 6 alkynylene,
  • G 3 is a C 3 -Ci 2 carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with one or more R G 3;
  • R G 3 is each independently, at each occurrence, halogen, -Ci-C 6 alkyl, -C(0)Ci-C 6 alkyl, -Q- C 6 haloalkyl, -0-Ci-C 6 alkyl, -0-Ci-C 6 haloalkyl, C 3 -C 6 carbocycle, or 3- to 6-membered heterocycle.
  • Z 3 is independently selected at each occurrence from N or CH, and Wi, W 2 , and W 3 are each independently selected at each occurrence from CH or N; A and B are each independently optionally substituted with one or more R A .
  • pyridinyl e.g., thiazolyl (e.g., and is optionally substituted with one or more R A .
  • both A and B are phenyl (e.g., both A and B are or A is
  • each A and B is independently optionally substituted with one or more R A .
  • a and B are substituted by one or more R A , wherein each R A is independently selected from halogen (e.g., fluoro, chloro), L S -R E (where L s is bond and R E is -Ci-C 6 alkyl (e.g., methyl), -O-Rs (e.g., -0-Ci-C 6 alkyl, -OCH 3 ), or -Ci-C 6 alkyl optionally substituted with one or more halogen (e.g., -CF 3 )), or L S -RE (where L S is Ci-Cealkylene and R E is -0-R s (e.g., -Ci-C 6 alk
  • A is and B is as defined hereinabove. In certain other embodiments B is
  • D is C 6 -Ci 0 carbocycle or 3- to 12- membered heterocycle optionally substituted by one or more R M .
  • D is C 6 -Ci 0 aryl (e.g., phenyl, naphthyl, indanyl), or 5- to 10-membered heteroaryl (pyridinyl, thiazolyl, 4,5,6,7- tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, benzo[d][l ,3]dioxol-5-yl), and D is substituted with one or more R M .
  • aryl e.g., phenyl, naphthyl, indanyl
  • 5- to 10-membered heteroaryl pyridinyl, thiazolyl, 4,5,6,7- tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl
  • D is preferably phenyl substituted by one or more R M , wherein each R M is independently halogen (e.g., fluoro, chloro, bromo); Ci-C 6 alkyl (e.g., tert-butyl); Ci-C 6 alkyl substituted with one or more halogen (e.g., CF 3 ); -O- Rs such as -O-Ci-Cealkyl (e.g., -0-CH 2 CH 3 ); or -O-Ci-Cealkyl substituted at each occurrence with one or more halogen (e.g., -O-CF3, -0-CH 2 CHF 2 ) or -0-C C 6 alkyl (e.g., -0-CH 2 CH 2 OCH 3 ); -O- R s (e.g., -0-Ci-C 6 alkyl, such as -0-CH 2 ) substituted with 3- to 12-membered heterocycle
  • each R M is
  • D is preferably phenyl or pyridyl and is substituted by one or more R M where one R M is G 2 .
  • D is substituted by G 2
  • G 2 is 3- to 12-membered heterocycle (e.g., pyridinyl, piperidinyl, pyrrolidinyl, azetidinyl, oxazolyl) and is optionally substituted with one or more halogen (e.g., fluoro, chloro), hydroxy, oxo, cyano, Ci-C 6 alkyl (e.g., methyl), C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 haloalkyl (e.g., CF 3 ), C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl,
  • D is phenyl or pyridyl and G 2 is, for example, a monocyclic 3-8 membered carbocycle or monocyclic 4-8 membered heterocycle substituted with L 4 -G 3 and optionally substituted with one or more R G2 wherein L 4 , G 3 and R G2 are as defined herein.
  • L 4 for example is a bond, a Ci-C 6 alkylene (e.g., -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - etc.), -0-, or -S(0) 2 - G 3 is for example a C 3 -Ci 2 carbocycle optionally substituted with one or more R G3 .
  • RG2 and R G3 are each independently at each occurrence halogen, -C(0)Ci-C 6 alkyl, -Ci-C 6 alkyl,
  • G 2 is ,
  • a monocyclic 4-8 membered nitrogen-containing heterocycle e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl
  • a monocyclic 4-8 membered nitrogen-containing heterocycle e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl
  • R G2 and G 3 is optionally substituted with R G3 .
  • R G3 can be, for example, 3-phenylazetidin- 1-yl, 3-phenylpyrrolidin-l-yl, 4-phenylpiperazin-l-yl, 4-phenylpiperidin-l-yl, 4-phenyl-3,6- dihydropyridin- 1 (2H)-yl, 4,4-diphenylpiperidin- 1 -yl, 4-acetyl-4-phenylpiperidin- 1 -yl, 4-(4- methoxyphenyl)piperidin-l-yl, 4-(4-fluorophenyl)piperidin-l-yl, or 3-phenylpiperidin-l-yl, and wherein D can be further optionally substituted with one or more R M (e.g., fluoro, chloro, methyl, methoxy).
  • R M e.g., fluoro, chloro, methyl, meth
  • L 4 is a C1-C6 alkylene, -0-, or -
  • S(0) 2 - and G 2 is , where is as defined above and is optionally substituted with R G 2
  • can be, for example, 4-tosylpiperazin-l-yl, 4-phenoxypiperidin-l-yl, 3-phenoxypyrrolidin-l-yl, 4-benzylpiperidin-l-yl, 4- phenethylpiperidin-l-yl, or 3-phenylpropyl)piperidin-l-yl.
  • D is phenyl or pyridyl
  • D is substituted by G 2 and G 2 is a spiro, bridged, or fused bicyclic carbocycle or heterocycle optionally substituted with L 4 -G 3 and one or more RG2, wherein D is optionally substituted with one or more R M
  • R M G 3 , and R G 2 are as defined herein.
  • R M G 3 , and R G 2 are as defined herein.
  • G 2 is
  • G 2 is 3-azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-2-yl, 6-azaspiro[2.5]oct-6-yl, octahydro-2H- isoindol-2-yl, 3-azaspiro[5.5]undec-3-yl, l,3-dihydro-2H-isoindol-2-yl, l,4-dioxa-8-azaspiro[4.5]dec- 8-yl) attached to the parent molecular moiety through a nitrogen atom and optionally substituted with G 3 and one or more R G 2-
  • G 2 is 3-azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-2-yl, 6- azaspiro[2.5]oct-6-yl, oc
  • R M can be fluoro, chloro, tert-butyl, -0-CH 2 CH 3 , -O-CF 3 , -O- CH 2 CHF 2 , -0-CH 2 CH 2 OCH 3 , -0-CH 2 -(3-ethyloxetan-3-yl), -0-CH 2 -(l,3-dioxolan-4-yl), -O- cyclopentyl, -O-cyclohexyl, -O-phenyl, -0-(l,3-dioxan-5-yl), cyclopropyl, cyclohexyl, phenyl, SF 5 , -S0 2 Me, or -N(t-Bu)C(0)Me and D can be optionally substituted by one or more additional R M selected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C 6
  • D is wherein R M is fluoro, chloro, tert-butyl, -0-CH 2 CH 3 , - O-CF 3 , -0-CH 2 CHF 2 , -0-CH 2 CH 2 OCH 3 , SF 5 , -S0 2 Me, or -N(t-Bu)C(0)Me and D is optionally substituted by one or more additional R M selected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C 6 alkyl (e.g., methyl).
  • D is wherein R M is cyclopropyl, cyclohexyl, or phenyl and D is optionally substituted by one or more additional R M selected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C 6 alkyl (e.g., methyl).
  • R M is cyclopropyl, cyclohexyl, or phenyl and D is optionally substituted by one or more additional R M selected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C 6 alkyl (e.g., methyl).
  • D is wherein R M is -0-CH 2 -(3-ethyloxetan-3-yl), -0-CH 2 -
  • R M selected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C 6 alkyl (e.g., methyl).
  • D is wherein G 2 is pyridinyl (e.g., pyridin-2-yl), piperidin-1- yl, 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l -yl, 2,6-dimethylpiperidin-l-yl, 4-(propan-2- yl)piperidin- 1 -yl, 4-fluoropiperidin- 1 -yl, 3 ,5 -dimethylpiperidin- 1 -yl, 4-(trifluoromethyl)piperidin- 1 - yl, 4-methylpiperidin-l-yl, 4-tert-butylpiperidin-l -yl, 2-oxopiperidin-l -yl, 3,3-dimethylazetidin-l -yl, or oxazolyl (e.g., l ,3-oxazol-2-yl) and D is optionally substituted by pyridin
  • D is wherein Gi is N,
  • G 2 wherein is a monocyclic 4-8 membered nitrogen-containing heterocycle (e.g., azetidinyl, pyrrolidinyl, piperidinyl) attached to the parent molecular moiety through a nitrogen atom and substituted by L 4 -G 3 and optionally substituted with one or more RG2;
  • L4 is a bond, Ci-C 6 alkylene, -0-, or -S(0) 2 -;
  • G 3 is aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), or heterocycle (e.g., thienyl) wherein each G3 is optionally substituted with one or more RG3;
  • Rc2 3 ⁇ 4nd RG3 at each occurrence are each independently halogen, -C(0)Ci-C 6 alkyl, -Ci-C 6 alkyl, -Ci-C 6 haloalkyl,
  • G 3 is phenyl optionally substituted with one or two R G 3; g is 0, 1, or 2; R M is each independently
  • D is wherein G 3 is phenyl optionally substituted with one or two R G 3; RMI is each independently hydrogen, fluoro, chloro, or methyl; and R G 2 is an optional substituent as described herein.
  • G 3 is phenyl optionally substituted with one or two R G 3; RMI is each independently hydrogen, fluoro, chloro, or methyl; and R G 2 is an optional substituent as described herein.
  • D is wherein L 4 is Ci-C 6 alkylene, -0-, or -
  • G 3 is phenyl optionally substituted with one or two R G 3; g is 0, 1, or 2; R M is each
  • R G 3 are as defined above.
  • D is wherein Gi is
  • R M1 is each independently hydrogen, fluoro, chloro, or methyl, and is as defined above (e.g., 3-azabicyclo[3.2.0]hept-3-yl, octahydro-2H-isoindol-2-yl, 2- azabicyclo[2.2.2]oct-2-yl, 6-azaspiro[2.5]oct-6-yl, 3-azaspiro[5.5]undec-3-yl, l ,3-dihydro-2H- isoindol-2-yl, l,4-dioxa-8-azaspiro[4.5]dec-8-yl).
  • D IS wherein is a monocyclic 4-8 membered nitrogen-containing heterocycle (e.g., azetidinyl, pyrrolidinyl, piperidinyl) substituted with one or more R G 2, wherein R G2 at each occurrence is each independently halogen, -C(0)Ci-C 6 alkyl, -Ci-C 6 alkyl, -Ci-C 6 haloalkyl, -0-Ci-C 6 alkyl, or -O-Ci- C 6 haloalkyl; and R M is each independently halogen, -Ci-C 6 alkyl, -Ci-C 6 haloalkyl, -0-Ci-C 6 alkyl, or
  • R G 2 is azetidinyl, pyrrolidinyl, or piperidinyl substituted with one or two R G 2, wherein R G 2 at each occurrence is each independently methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, or trifluoromethyl; and R M is each independently fluoro, chloro, or methyl.
  • R G 2 at each occurrence is each independently methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, or trifluoromethyl
  • R M is each independently fluoro, chloro, or methyl.
  • 4-dimethylpiperidin-l-yl is 4,4-dimethylpiperidin-l-yl
  • X is pyrrolyl and is attached to the remainder of the molecule as shown in Formula
  • X is pyrrolidinyl and is attached to the remainder of the molecule as shown in Formula X B : .
  • Embodiments according to Formula X B may exist
  • X B , XBI, and X B2 may have either the (R) or (S) absolute stereochemistry.
  • X is pyrrolyl and is attached to the
  • X is rrolidinyl and is attached to the remainder of the molecule as shown
  • Formulae X D i or X D2 may exist in cis or trans forms and chiral carbon atoms in X D i and X D2 may have either the (R) or (S) absolute stereochemistry.
  • X is azetidinyl and is attached to the remainder molecule as shown in Formulae X E i or X E2 :
  • Chiral carbon atoms in X E i and X E2 may independently have either the (R) or (S) absolute stereochemistry.
  • X is X A , XB, XBI, XB 2 , XCI, or X C2 and L u L 2 , and L 3 are each a bond.
  • X is X D i, XD 2 , XEI, or X E2 and Li, L 2 , and L3 are each a bond.
  • X is X E i and Li and L 2 are each methylene (i.e. -CH 2 -), and L 3 is a bond.
  • Y is-T'-C(RiR 2 )N(R 5 )-T-RD and Z is -T'-C(R 8 R9)N(Ri 2 )-T- R D ; wherein T', R l s R 2 , R 5 , Rs, R9, R12, T, and R D are as defined herein.
  • Ri, R 2 , R5, Rs, R9, and R12 are each independently hydrogen; Ci-C 6 alkyl; or 3- to 6- membered carbocycle or heterocycle, wherein each 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from halogen or Ci-Cealkyl; wherein R 2 and R 5 , taken together with the atoms to which they are attached, optionally form a 3- to 12-membered heterocycle which is substituted with 0, 1, 2, 3, or 4 R A , and R 9 and Ri 2 taken together with the atoms to which they are attached, optionally form a 3- to 12- membered heterocycle which is substituted with 0, 1, 2, 3, or 4 R A wherein R A is as defined herein.
  • Ri is hydrogen and R 2 and R 5 , taken together with the atoms to which they are attached form a 3- to 12-membered heterocycle (e.g.,
  • R A is halogen (e.g., fluoro, chloro); cyano; L S -R E where L S is a single bond and R E is Ci-Cealkyl (e.g., methyl, ethyl), -0-Ci-C 6 alkyl (e.g., methoxy), or -0-Ci-C 6 hal trifluoromethoxy); or L s -
  • R A is fluoro, methoxy, methyl, ethyl, or cyano.
  • R 5 taken together with the atoms to which they are
  • R 8 is hydrogen and R9 and Ri 2 , taken together with the atoms to which they are attached form a 3- to 12-membered heterocycle (e.g.,
  • a pyrrolidine ring i.e., substituted with 0 or 1 R A wherein R A is fluoro, methoxy, methyl, ethyl, or cyano.
  • a chiral carbon in any rings formed by joining R 2 and R 5 or R 9 and R12 may
  • R 5 or R 9 and R12 preferably possesses the (S) stereochemistry
  • R B is independently selected at each occurrence from a bond,- C(0)N(R B )-, -N(R B )C(0)-, or 3- to 12-membered heterocycle, and wherein said 3- to 12-membered heterocycle is each independently optionally substituted at each occurrence with one or more R A , and R A and R B are as described herein.
  • R B can be hydrogen (i.e.,
  • T' is -C(0)N(H)-).
  • T' is imidazolyl (i.e., — N , N— ) optionally substituted at each occurrence with one or more R A wherein R A is halogen (e.g., fluoro, chloro), Ci Cealkyl (e.g., methyl, ethyl), or Ci-Cehaloalkyl (e.g., trifluoromethyl).
  • R A is halogen (e.g., fluoro, chloro), Ci Cealkyl (e.g., methyl, ethyl), or Ci-Cehaloalkyl (e.g., trifluoromethyl).
  • is imidazolyl i.e.,
  • This aspect of the invention contemplates particular combinations of A with Y and B with Z.
  • A is C 5 -C 6 carbocycle (e.g., phenyl) or 5- to 6-membered heterocycle (e.g., pyridinyl or thiazolyl)
  • preferred Z when B is C 5 -C 6 carbocycle (e.g., phenyl) or
  • T and R D are as defined herein.
  • A is optionally substituted with one or more R A as described herein, or Y-A is and non-limiting wherein T and R D are as defined herein.
  • T and R D are as defined herein.
  • T at each occurrence is independently a bond or -C(0)-L s '-, wherein L s ' is as defined herein.
  • L s ' includes, but is not limited to, , , or , where L s ' is optionally substituted with one or more R L ; and R L is a substituent such as, but not limited to carbocycle (e.g., cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl), methoxy, or heterocycle (e.g., tetrahydrofuranyl, tetrahydropyranyl).
  • carbocycle e.g., cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl
  • heterocycle e.g., tetrahydrofuranyl, tetrahydropyranyl.
  • R D is hydrogen or R A wherein R A is as defined herein.
  • R D includes, but is not limited to, R A wherein R A is L S -R E , and L s and R E are as defined herein.
  • R D includes, but is not limited to, LS-RE wherein L s is a bond and R E is-N(R s R s '), -N(R s )C(0)R s ', -N(R s )C(0)N(R s 'R s "), - N(R s )S0 2 Rs', — N(R s )S0 2 N(R s 'Rs"), -N(R s )S(0)N(R s 'R s "), -N(R s )C(0)OR s ', or -N(R s )S(0)- R s '; or C 3 -Ci 2 carbocycle or 3- to 12-membered hetero
  • R D is LS-RE wherein Ls is a bond and RE is -N(R s )C(0)OR s ' or 3- to 12-membered heterocycle (e.g., pyrrolidine, piperidine, azepanyl) wherein Rs and Rs' are as defined herein.
  • R D is preferably L S -RE wherein L s is a bond and R E is -N(H)C(0)OMe.
  • T-R D includes, but is not limited to:
  • non-limiting examples of preferred Y when A is C 5 - C 6 carbocycle (e.g., phenyl) or 5- to 6-membered heterocycle (e.g., pyridinyl or thiazolyl) and preferred Z when B is C 5 -C 6 carbocycle (e.g., phenyl) or 5- to 6-membered heterocycle (e.g., pyridinyl or thiazolyl) include:
  • the present invention features compounds of Formula harmaceutically acceptable salts thereof: wherein:
  • X is rein X is optionally substituted with one or more R A nally substituted with one or more RA;
  • B is or , wherein B is optionally substituted with one or more R A ; and Y, Z, R A , and D are as described hereinabove (e.g., Y, Z, R A , and D as described for Formula I, I A , IB, IC, ID, or I E , preferably as described for Formula I E ).
  • X is A is s , wherein B is optionally substituted with one or more R A ; Y is
  • D, R A , T and R D are as defined hereinabove (e.g., as described for Formula I, I A , 3 ⁇ 4, Ic, ID or I E , preferably as described for Formula I E ).
  • a or B are optionally substituted with one or more substituents selected from: R A wherein R A is each independently halogen (e.g., fluoro, chloro); L S -R E where L s is a single bond, and R E is -Ci-Cealkyl (e.g., methyl), -O-Rs (e.g., -0-Ci-C 6 alkyl, -OCH 3 ), or -Ci-C 6 alkyl optionally substituted with one or more halogen (e.g., - CF 3 ); or L S -R E where L s is a Ci-C 6 alkylene and R E is -O-Rs (e.g., -Ci-C 6 alkyl-0-Ci-C 6 alkyl, - CH 2 OCH 3 ).
  • R A is each independently halogen (e.g., fluoro, chloro)
  • L S -R E where L s is a single
  • This embodiment includes compounds where A and B are both substituted by one R A ; compounds where A and B are both substituted by zero R A ; compounds where A is substituted by one R A and B is substituted by zero R A ; and compounds where A is substituted by zero R A and B is
  • T-R D is independently selected at
  • this aspect of the invention features compound of Formula I F and pharmaceutically acceptable salts thereof, wherein: X is wherein A is optionally
  • B is wherein B is optionally substituted with one or
  • a particular subgroup according to this embodiment includes compounds where A is
  • this aspect of the invention features compounds of Formula I F and
  • D is , where R M is fluoro, chloro, tert-butyl, -O- CH 2 CH 3 , -O-CF3, -0-CH 2 CHF 2 , -0-CH 2 CH 2 OCH 3 , -0-CH 2 -(3-ethyloxetan-3-yl), -0-CH 2 -(l ,3- dioxolan-4-yl), -O-cyclopentyl, -O-cyclohexyl, -O-phenyl, -0-(l,3-dioxan-5-yl), cyclopropyl, cyclohexyl, phenyl, SF 5 , -S0 2 Me, or -N(t-Bu)C(0)Me and D is optionally substituted by one or more additional R M , selected from the group consisting of halogen (e.g., fluoro, chloro) or Ci-C 6 alkyl (e
  • D is wherein G 2 is pyridinyl (e.g., pyridin-2-yl), piperidin-l-yl, 4,4-dimethylpiperidin-l -yl, 4,4-difluoropiperidin-l -yl, 2,6-dimethylpiperidin-l-yl, 4- (propan-2-yl)piperidin-l-yl, 4-fluoropiperidin-l -yl, 3,5-dimethylpiperidin-l-yl, 4-
  • G 2 is pyridinyl (e.g., pyridin-2-yl), piperidin-l-yl, 4,4-dimethylpiperidin-l -yl, 4,4-difluoropiperidin-l -yl, 2,6-dimethylpiperidin-l-yl, 4- (propan-2-yl)piperidin-l-yl, 4-fluoropiperidin-l -yl, 3,5-dimethylpiperidin-
  • G 2 is piperidin-l-yl, 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 2,6- dimethylpiperidin-l -yl, 4-(propan-2-yl)piperidin-l -yl, 4-fluoropiperidin-l -yl, 3,5-dimethylpiperidin- l -yl, 4-(trifluoromethyl)piperidin-l -yl, 4-methylpiperidin- 1 -yl, 4-tert-butylpiperidin- 1-yl, 2- oxopiperidin-l-yl, or 3,3-dimethylazetidin-l -yl; and R M i is each independently hydrogen, fluoro, chloro, or methyl.
  • D wherein Gi is N, C-H, or C-R M ;
  • G 2 is , wherein , R M , and g are as defined hereinabove.
  • R M is each independently fluoro, chloro, methyl, methoxy, tnfluoromethyl, or
  • R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or
  • R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1 , or 2.
  • R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1 , or 2.
  • L 4 is Ci-C 6 alkylene, -0-, or -S(0) 2 -; G 2 is ⁇ ; R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2.
  • R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1 , or 2.
  • G 3 is phenyl optionally substituted with one or two R G 3; g is 0, 1, or 2; R M is each independently fluoro, chloro, methyl, methoxy,
  • compounds D is is Ci-C 6 alkylene, -0-, or -S(0) 2 -;
  • G 3 is phenyl optionally substituted with one or two R G 3;
  • g is 0, 1 , or 2;
  • R M is each independently fluoro, chloro, methyl,
  • G 3 is phenyl optionally substituted with one or two R G 3 as defined hereinabove;
  • R M i is each independently hydrogen, fluoro, chloro, or methyl;
  • RG2 is an optional substituent, as described above, selected from the group consisting of -C(0)Ci- C 6 alkyl, -C C 6 alkyl, -C C 6 haloalkyl, -0-C C 6 alkyl, and -O-d-Cghaloalkyl.
  • D is wherein Gi is N, C-H, or C-R M ; G 2 is
  • R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or
  • g is 0, 1 , or 2; and is 3-azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-
  • R M is each independently fluoro, chloro, methyl, methoxy,
  • compounds D is each independently hydrogen, fluoro, chloro, or
  • methyl and is as defined above (e.g., 3-azabicyclo[3.2.0]hept-3-yl, octahydro-2H-isoindol-2- yl, 2-azabicyclo[2.2.2]oct-2-yl, 6-azaspiro[2.5]oct-6-yl, 3-azaspiro[5.5]undec-3-yl, l,3-dihydro-2H- isoindol-2-yl, l,4-dioxa-8-azaspiro[4.5]dec-8-yl).
  • D is is a monocyclic
  • R G2 at each occurrence is each independently halogen, -C(0)Cr C 6 alkyl, -Ci-C 6 alkyl, -Ci-C 6 haloalkyl, -0-Ci-C 6 alkyl, or -0-Ci-C 6 haloalkyl; and R M is each independently halogen, -Ci-Cealkyl, -Ci-Cehaloalkyl, -O-Ci-Cealkyl, or -O-Ci-Cehaloalkyl.
  • R G2 at each occurrence is each independently halogen, -C(0)Cr C 6 alkyl, -Ci-C 6 alkyl, -Ci-C 6 haloalkyl, -0-Ci-C 6 alkyl, or -0-Ci-C 6 haloalkyl
  • R M is each independently halogen, -Ci-Cealkyl, -Ci-Cehaloal
  • R G2 at each occurrence is each methyl, ethyl, isopropyl, t trifluoromethyl; and R M is each independently fluoro, chloro,
  • the present invention features compounds of Formula I G and pharmaceutically acceptable salts thereof, wherein:
  • X is , wherein X is optionally substituted with one or more R
  • A is or , wherein A is optionally substituted with one or more R A ;
  • B is wherein B is optionally substituted with one or more R A ;
  • Y, Z, R A , and D are as described hereinabove (e.g., as described for Formula I, I A , 3 ⁇ 4, Ic, ID, IE or I F , preferably as described for Formula I E ).
  • this aspect of the invention features compounds of Formula I G and
  • A is optionally substituted with R A ;
  • B is or , wherein B is optionally substituted with one R A ;
  • R A is halogen (e.g., fluoro, chloro); L S -R E where L s is a single bond and R E is -Ci-C 6 alkyl (e.g., methyl), -0-R s (e.g., -0-Ci-C 6 alkyl, -OCH 3 ), or -Ci-C 6 alkyl optionally substituted with one or more halogen (e.g., -CF 3 ); or L S -R E where L s is a Ci-C 6 alkylene and R E is -0-R s (e.g., -Ci-C 6 alkyl-
  • Y and Z are each independently
  • T-R D is each independently ; and D is as defined hereinabove.
  • this aspect of the invention features compounds of Formula I G and
  • Y and Z are each independently R
  • This subgroup includes compounds where A and B are both substituted by one R A ; compounds where A and B are both substituted by zero R A ; compounds where A is substituted by one R A and B is substituted by zero R A ; and compounds where A is substituted by zero R A and B is substituted by one R A .
  • Groups of compounds according to this aspect of the invention include compounds where D is C 6 -Ci 0 aryl (e.g., phenyl, naphthyl, indanyl), or 5- to 10-membered heteroaryl (pyridinyl, thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, benzo[d][l,3]dioxol-5-yl), and D is substituted with one or more R M .
  • D is C 6 -Ci 0 aryl (e.g., phenyl, naphthyl, indanyl), or 5- to 10-membered heteroaryl (pyridinyl, thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, benzo[d][l,3]diox
  • R M is halogen (e.g., fluoro, chloro, bromo); Ci-C 6 alkyl (e.g., tert-butyl); Ci-C 6 alkyl substituted with one or more halogen (e.g., CF 3 ); -0-Ci-C 6 aikyl (e.g., - 0-CH 2 CH 3 ); -0-Ci-C 6 alkyl substituted at each occurrence with one or more halogen (e.g., -O-CF 3 , -0-CH 2 CHF 2 ) or -0-C C 6 alkyl (-0-CH 2 CH 2 OCH 3 ); -0-C C 6 alkyl (e.g., -0-CH 2 ) substituted with an optionally substituted 3- to 12-membered heterocycle (e.g., 3-ethyloxetan-3-yl, 1,3-dioxolan- 4-y
  • R M is halogen (e.g., flu
  • Other subgroups according to this embodiment include compounds wherein D is phenyl substituted by G 2 and optionally substituted by one or more R M , wherein G 2 is a 3- to 12-membered heterocycle (e.g., pyridinyl, piperidinyl, pyrrolidinyl, azetidinyl, oxazolyl) wherein the heterocycle is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, cyano, Ci-Cealkyl (e.g., methyl), C 2 -Cealkenyl, C 2 - Cealkynyl, Ci-Cehaloalkyl (e.g., CF 3 ), C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, -O-Ci-Cealkyl (e.g., -O- CH 3 ), -C(0)OR s (e.g.
  • D is , where R M is fluoro, chloro, tert-butyl, -O-
  • D is wherein G 2 is pyridinyl (e.g., pyridin-2-yl), piperidin-l-yl, 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 2,6-dimethylpiperidin-l-yl, 4-
  • G 2 is pyridinyl (e.g., pyridin-2-yl), piperidin-l-yl, 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 2,6-dimethylpiperidin-l-yl, 4-
  • G 2 is piperidin-l-yl, 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 2,6- dimethylpiperidin-l-yl, 4-(propan-2-yl)piperidin-l -yl, 4-fluoropiperidin- 1 -yl, 3,5-dimethylpiperidin- 1 -yl, 4-(trifluoromethyl)piperidin-l-yl, 4-methylpiperidin- 1-yl, 4-tert-butylpiperidin- 1-yl, 2- oxopiperidin-l-yl, or 3,3-dimethylazetidin-l-yl; and R M i is each independently hydrogen, fluoro, chloro, or methyl.
  • R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or
  • G 2 is ⁇ ;
  • R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or
  • is 3-phenylazetidin-l -yl, 3- phenylpyrrolidin- 1 -yl, 4-phenylpiperazin- 1 -yl, 4-phenylpiperidin- 1 -yl, 4-phenyl-3 ,6-dihydropyridin- 1 (2H)-yl, 4,4-diphenylpiperidin- 1 -yl, 4-acetyl-4-phenylpiperidin- 1 -yl, 4-(4-methoxyphenyl)piperidin- 1 -yl, 4-(4-fluorophenyl)piperidin-l-yl, or 3-phenylpiperidin-l-yl; R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1 , or 2. In other subgroups, R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or
  • L 4 is Ci-C 6 alkylene, -0-, or -S(0) 2 -; G 2 is ; R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2.
  • G 2 is ; R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2.
  • R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy
  • g is 0, 1 , or
  • compounds D is 6 alkylene, -0-, or -S(0) 2 -;
  • G 3 is phenyl optionally substituted with one or two R G 3;
  • g is 0, 1 , or 2;
  • R M is each independently fluoro, chloro, methyl,
  • G 3 is phenyl optionally substituted with one or two R G 3 as defined hereinabove;
  • R M i is each independently hydrogen, fluoro, chloro, or methyl;
  • RG 2 is an optional substituent, as described above, selected from the group consisting of -C(0)Ci- C 6 alkyl, -Ci-C 6 alkyl, -Ci-C 6 haloalkyl, -0-Ci-C 6 alkyl, and -0-Ci-C 6 haloalkyl.
  • D is wherein Gi is N, C-H, or C-R M ; G 2 is
  • R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or
  • g is 0, 1 , or 2; and is 3-azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-
  • R M is each independently fluoro, chloro, methyl, methoxy,
  • compounds D is each independently hydrogen, fluoro, chloro, or
  • methyl and is as defined above (e.g., 3-azabicyclo[3.2.0]hept-3-yl, octahydro-2H-isoindol-2- yl, 2-azabicyclo[2.2.2]oct-2-yl, 6-azaspiro[2.5]oct-6-yl, 3-azaspiro[5.5]undec-3-yl, l,3-dihydro-2H- isoindol-2-yl, l,4-dioxa-8-azaspiro[4.5]dec-8-yl).
  • D is is a monocyclic
  • R G2 at each occurrence is each independently halogen, -C(0)Cr C 6 alkyl, -Ci-C 6 alkyl, -Ci-C 6 haloalkyl, -0-Ci-C 6 alkyl, or -0-Ci-C 6 haloalkyl; and R M is each independently halogen, -Ci-Cealkyl, -Ci-Cehaloalkyl, -O-Ci-Cealkyl, or -O-Ci-Cehaloalkyl.
  • R G2 at each occurrence is each independently halogen, -C(0)Cr C 6 alkyl, -Ci-C 6 alkyl, -Ci-C 6 haloalkyl, -0-Ci-C 6 alkyl, or -0-Ci-C 6 haloalkyl
  • R M is each independently halogen, -Ci-Cealkyl, -Ci-Cehaloal
  • R G2 at each occurrence is each methyl, ethyl, isopropyl, t trifluoromethyl; and R M is each independently fluoro, chloro,
  • the present invention also features compounds of Formulae I E , IF and IG as described herein (including each embodiment described hereunder) and pharmaceutically acceptable salts thereof, wherein:
  • R E is independently selected at each occurrence from -0-R s , -S-R s , -C(0)R s , -OC(0)R s , -
  • the compounds of the present invention can be used in the form of salts.
  • a salt of a compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability under certain conditions or desired solubility in water or oil.
  • a salt of a compound may be useful for the isolation or purification of the compound.
  • the salt preferably is pharmaceutically acceptable.
  • Pharmaceutically acceptable salts include, but are not limited to, acid addition salts, base addition salts, and alkali metal salts.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids.
  • suitable inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroionic, nitric, carbonic, sulfuric, and phosphoric acid.
  • suitable organic acids include, but are not limited to, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic, and sulfonic classes of organic acids.
  • suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylammosulfonate, algenic acid, b-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, buty
  • Pharmaceutically acceptable base addition salts include, but are not limited to, metallic salts and organic salts.
  • suitable metallic salts include alkali metal (group la) salts, alkaline earth metal (group Ila) salts, and other pharmaceutically acceptable metal salts.
  • Such salts may be made, without limitation, from aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc.
  • suitable organic salts can be made from tertiary amines and quaternary amine, such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
  • Basic nitrogen-containing groups can be quatemized with agents such as alkyl halides (e.g., methyl, ethyl, propyl, butyl, decyl, lauryl, myristyl, and stearyl chlorides/bromides/iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • alkyl halides e.g., methyl, ethyl, propyl, butyl, decyl, lauryl, myristyl, and stearyl chlorides/bromides/iodides
  • dialkyl sulfates e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates
  • the compounds or salts of the present invention may exist in the form of solvates, such as with water (i.e., hydrates), or with organic solvents (e.g., with methanol, ethanol or acetonitrile to form, respectively, methanolate, ethanolate or acetonitrilate).
  • solvates such as with water (i.e., hydrates), or with organic solvents (e.g., with methanol, ethanol or acetonitrile to form, respectively, methanolate, ethanolate or acetonitrilate).
  • the compounds or salts of the present invention may also be used in the form of prodrugs.
  • Some prodrugs are aliphatic or aromatic esters derived from acidic groups on the compounds of the invention. Others are aliphatic or aromatic esters of hydroxyl or amino groups on the compounds of the invention. Phosphate prodrugs of hydroxyl groups are preferred prodrugs.
  • the compounds of the invention may comprise asymmetrically substituted carbon atoms known as chiral centers. These compounds may exist, without limitation, as single stereoisomers (e.g., single enantiomers or single diastereomer), mixtures of stereoisomers (e.g. a mixture of enantiomers or diastereomers), or racemic mixtures.
  • stereoisomer a compound that is present in a form that is substantially free from other stereoisomers (e.g., substantially free from other enantiomers or diastereomers).
  • substantially free it means that at least 80% of the compound in a composition is the described stereoisomer; preferably, at least 90%> of the compound in a composition is the described stereoisomer; and more preferably, at least 95%, 96%, 97%>, 98%> or 99%o of the compound in a composition is the described stereoisomer.
  • the stereochemistry of a chiral carbon is not specified in the chemical structure of a compound, the chemical structure is intended to encompass compounds containing either stereoisomer of the chiral center.
  • Individual stereoisomers of the compounds of this invention can be prepared using a variety of methods known in the art. These methods include, but are not limited to, stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of enantiomers in an enantiomeric mixture to diastereomers followed by chromatographically separation of the diastereomers and regeneration of the individual enantiomers, and enzymatic resolution.
  • Stereospecific synthesis typically involves the use of appropriate optically pure (enantiomerically pure) or substantial optically pure materials and synthetic reactions that do not cause racemization or inversion of stereochemistry at the chiral centers.
  • Mixtures of stereoisomers of compounds, including racemic mixtures, resulting from a synthetic reaction may be separated, for example, by chromatographic techniques as appreciated by those of ordinary skill in the art. Chromatographic resolution of enantiomers can be accomplished by using chiral chromatography resins, many of which are commercially available.
  • racemate is placed in solution and loaded onto the column containing a chiral stationary phase. Enantiomers can then be separated by HPLC.
  • Resolution of enantiomers can also be accomplished by converting enantiomers in a mixture to diastereomers by reaction with chiral auxiliaries.
  • the resulting diastereomers can be separated by column chromatography or crystallization/re-crystallization. This technique is useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group that will form a salt or covalent bond with the chiral auxiliary.
  • suitable chiral auxiliaries include chirally pure amino acids, organic carboxylic acids or organosulfonic acids.
  • Enzymes such as esterases, phosphatases or lipases, can be useful for the resolution of derivatives of enantiomers in an enantiomeric mixture.
  • an ester derivative of a carboxyl group in the compounds to be separated can be treated with an enzyme which selectively hydrolyzes only one of the enantiomers in the mixture.
  • the resulting enantiomerically pure acid can then be separated from the unhydrolyzed ester.
  • salts of enantiomers in a mixture can be prepared using any suitable method known in the art, including treatment of the carboxylic acid with a suitable optically pure base such as alkaloids or phenethylamine, followed by precipitation or crystallization/re-crystallization of the enantiomerically pure salts.
  • a suitable optically pure base such as alkaloids or phenethylamine
  • Methods suitable for the resolution/separation of a mixture of stereoisomers, including racemic mixtures can be found in ENANTIOMERS, RACEMATES, AND RESOLUTIONS (Jacques et al, 1981, John Wiley and Sons, New York, NY).
  • a compound of this invention may possess one or more unsaturated carbon-carbon double bonds. All double bond isomers, such as the cis (Z) and trans (E) isomers, and mixtures thereof are intended to be encompassed within the scope of a recited compound unless otherwise specified. In addition, where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms.
  • Certain compounds of the invention may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotations about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
  • the invention encompasses each conformational isomer of these compounds and mixtures thereof.
  • Certain compounds of the invention may also exist in zwitterionic form and the invention encompasses each zwitterionic form of these compounds and mixtures thereof.
  • the compounds of the present invention are generally described herein using standard nomenclature. For a recited compound having asymmetric center(s), it should be understood that all of the stereoisomers of the compound and mixtures thereof are encompassed in the present invention unless otherwise specified. Non-limiting examples of stereoisomers include enantiomers, diastereomers, and cis-transisomers. Where a recited compound exists in various tautomeric forms, the compound is intended to encompass all tautomeric forms. Certain compounds are described herein using general formulas that include variables (e.g., A, B, D, X, Li, L 2 , L 3 , Y, Z, T, R A or R B ,).
  • variables e.g., A, B, D, X, Li, L 2 , L 3 , Y, Z, T, R A or R B ,).
  • each variable within such a formula is defined independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence. If moieties are described as being "independently" selected from a group, each moiety is selected independently from the other. Each moiety therefore can be identical to or different from the other moiety or moieties.
  • C x -C y The number of carbon atoms in a hydrocarbyl moiety can be indicated by the prefix "C x -C y ,” where x is the minimum and y is the maximum number of carbon atoms in the moiety.
  • Ci-Cealkyl refers to an alkyl substituent containing from 1 to 6 carbon atoms.
  • C3-Cecycloalkyl means a saturated hydrocarbyl ring containing from 3 to 6 carbon ring atoms.
  • a prefix attached to a multiple-component substituent only applies to the first component that immediately follows the prefix.
  • the term "carbocyclylalkyl” contains two components: carbocyclyl and alkyl.
  • C3-C 6 carbocyclylCi-C 6 alkyl refers to a C 3 -C 6 carbocyclyl appended to the parent molecular moiety through a Ci-Cealkyl group.
  • a linking element links two other elements in a depicted chemical structure
  • the leftmost-described component of the linking element is bound to the left element in the depicted structure
  • the rightmost-described component of the linking element is bound to the right element in the depicted structure.
  • the chemical structure is -L s -M- Ls'- and M is -N(R B )S(0)- then the chemical structure is -L s -N(R B )S(0)-L s '-.
  • a linking element in a depicted structure is a bond
  • the element left to the linking element is joined directly to the element right to the linking element via a covalent bond.
  • a chemical structure is depicted as -L s -M-L s '- and M is selected as bond
  • the chemical structure will be -L s -L s '-.
  • two or more adjacent linking elements in a depicted structure are bonds, then the element left to these linking elements is joined directly to the element right to these linking elements via a covalent bond.
  • the dash(s) indicates the portion of the moiety that has the free valence(s).
  • a moiety is described as being “optionally substituted", the moiety may be either substituted or unsubstituted. If a moiety is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that moiety may be either unsubstituted, or substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the moiety, whichever is less. Thus, for example, if a moiety is described as a heterocycle optionally substituted with up to three non-hydrogen radicals, then any heterocycle with less than three substitutable positions will be optionally substituted by up to only as many non- hydrogen radicals as the heterocycle has substitutable positions.
  • tetrazolyl (which has only one substitutable position) will be optionally substituted with up to one non-hydrogen radical.
  • an amino nitrogen is described as being optionally substituted with up to two non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to two non-hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only one non-hydrogen radical.
  • alkenyl means a straight or branched hydrocarbyl chain containing one or more double bonds. Each carbon-carbon double bond may have either cis or trans geometry within the alkenyl moiety, relative to groups substituted on the double bond carbons.
  • alkenyl groups include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl.
  • alkenylene refers to a divalent unsaturated hydrocarbyl chain which may be linear or branched and which has at least one carbon-carbon double bond.
  • alkyl means a straight or branched saturated hydrocarbyl chain.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t- butyl, pentyl, iso-amyl, and hexyl.
  • alkylene denotes a divalent saturated hydrocarbyl chain which may be linear or branched.
  • Representative examples of alkylene include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and -CH 2 CH(CH 3 )CH 2 -.
  • alkynyl means a straight or branched hydrocarbyl chain containing one or more triple bonds.
  • Non-limiting examples of alkynyl include ethynyl, 1-propynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, and 3-butynyl.
  • alkynylene refers to a divalent unsaturated hydrocarbon group which may be linear or branched and which has at least one carbon-carbon triple bonds.
  • Representative alkynylene groups include, by way of example, — C ⁇ C— , — C ⁇ C— CH 2 — , — C ⁇ C— CH 2 — CH 2 — , -CH 2 -C ⁇ C-CH 2 - -C ⁇ C-CH(CH 3 )-, and -CH 2 -C ⁇ C-CH(CH 2 CH 3 )-.
  • Carbocycle or “carbocyclic” or “carbocyclyl” refers to a saturated (e.g., “cycloalkyl"), partially saturated (e.g., “cycloalkenyl” or “cycloalkynyl") or completely unsaturated (e.g., "aryl”) ring system containing zero heteroatom ring atom.
  • Ring atoms or “ring members” are the atoms bound together to form the ring or rings.
  • a carbocyclyl may be, without limitation, a single ring, two fused rings, or bridged or spiro rings.
  • a substituted carbocyclyl may have either cis or trans geometry.
  • carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl, cyclohexadienyl, adamantyl, decahydro-naphthalenyl, octahydro-indenyl, cyclohexenyl, phenyl, naphthyl, indanyl, 1,2,3,4-tetrahydro-naphthyl, indenyl, isoindenyl, decalinyl, and norpinanyl.
  • a carbocycle group can be attached to the parent molecular moiety through any substitutable carbon ring atom.
  • a carbocycle group is a divalent moiety linking two other elements in a depicted chemical structure (such as A in Formula I)
  • the carbocycle group can be attached to the two other elements through any two substitutable ring atoms.
  • a carbocycle group is a trivalent moiety linking three other elements in a depicted chemical structure (such as X in Formula I)
  • the carbocycle group can be attached to the three other elements through any three substitutable ring atoms, respectively.
  • Carbocyclylalkyl refers to a carbocyclyl group appended to the parent molecular moiety through an alkylene group.
  • C3-C 6 carbocyclylCi-C 6 alkyl refers to a C3- C 6 carbocyclyl group appended to the parent molecular moiety through Ci-C 6 alkylene.
  • cycloalkenyl refers to a non-aromatic, partially unsaturated carbocyclyl moiety having zero heteroatom ring member.
  • Representative examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, and octahydronaphthalenyl.
  • cycloalkyl refers to a saturated carbocyclyl group containing zero heteroatom ring member.
  • Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decalinyl and norpinanyl.
  • Ci-Cehaloalkyl means a Ci-C 6 alkyl substituent wherein one or more hydrogen atoms are replaced with independently selected halogen radicals.
  • Non-limiting examples of Ci-Cehaloalkyl include chloromethyl, 1-bromoethyl, fluorom ethyl, difluoromethyl, trifluorom ethyl, and 1,1 ,1-trifluoroethyl. It should be recognized that if a substituent is substituted by more than one halogen radical, those halogen radicals may be identical or different (unless otherwise stated).
  • heterocycle or “heterocyclo” or “heterocyclyl” refers to a saturated (e.g., “heterocycloalkyl"), partially unsaturated (e.g., “heterocycloalkenyl” or “heterocycloalkynyl”) or completely unsaturated (e.g., “heteroaryl”) ring system where at least one of the ring atoms is a heteroatom (i.e., nitrogen, oxygen or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur.
  • a heterocycle may be, without limitation, a single ring, two fused rings, or bridged or spiro rings.
  • a heterocycle group can be linked to the parent molecular moiety via any substitutable carbon or nitrogen atom(s) in the group.
  • a heterocycle group is a divalent moiety that links two other elements in a depicted chemical structure (such as A in Formula I)
  • the heterocycle group can be attached to the two other elements through any two substitutable ring atoms.
  • a heterocycle group is a trivalent moiety that links three other elements in a depicted chemical structure (such as X in Formula I)
  • the heterocycle group can be attached to the three other elements through any three substitutable ring atoms, respectively.
  • a heterocyclyl may be, without limitation, a monocycle which contains a single ring.
  • monocycles include furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl
  • a heterocyclyl may also be, without limitation, a bicycle containing two fused rings, such as, for example, naphthyridinyl (including [1,8] naphthyridinyl, and [1,6] naphthyridinyl), thiazolpyrimidinyl, thienopyrimidinyl, pyrimidopyrimidinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, and pyrido[4,3-b]-pyridinyl), pyridopyrimidine, and pteridinyl.
  • naphthyridinyl including [1,8]
  • fused-ring heterocycles include benzo-fused heterocyclyls, such as indolyl, isoindolyl, indoleninyl (also known as “pseudoindolyl”), isoindazolyl (also known as “benzpyrazolyl” or indazolyl), benzazinyl (including quinolinyl (also known as “1- benzazinyl”) and isoquinolinyl (also known as “2 -benzazinyl”)), benzimidazolyl, phthalazinyl, quinoxalinyl, benzodiazinyl (including cinnolinyl (also known as “1,2-benzodiazinyl”) and quinazolinyl (also known as "1,3 -benzodiazinyl”)), benzopyranyl (including “chromenyl” and “isochromenyl”), benzothiopyranyl (also known as "thiochromenyl”)
  • a heterocyclyl may also be, without limitation, a spiro ring system, such as, for example, 1,4- dioxa-8-azaspiro[4.5]decanyl.
  • a heterocyclyl may comprise one or more sulfur atoms as ring members; and in some cases, the sulfur atom(s) is oxidized to SO or SO2.
  • the nitrogen heteroatom(s) in a heterocyclyl may or may not be quaternized, and may or may not be oxidized to N-oxide. In addition, the nitrogen heteroatom(s) may or may not be N-protected.
  • ⁇ z m a chemical formula refers to a single or double bond.
  • pharmaceutically acceptable is used adjectivally to mean that the modified noun is appropriate for use as a pharmaceutical product or as a part of a pharmaceutical product.
  • terapéuticaally effective amount refers to the total amount of each active substance that is sufficient to show a meaningful patient benefit, e.g. a reduction in viral load.
  • prodrug refers to derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become, by solvolysis or under physiological conditions, the compounds of the invention which are pharmaceutically active in vivo.
  • a prodrug of a compound may be formed in a conventional manner by reaction of a functional group of the compound (such as an amino, hydroxy, carboxy or phosphate group).
  • Prodrugs often offer advantages of solubility, tissue compatibility, or delayed release in mammals (see, Bungard, H., DESIGN OF PRODRUGS, pp. 7-9, 21 -24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine.
  • Examples of prodrugs include, but are not limited to, acetate, formate, benzoate or other acylated derivatives of alcohol or amine functional groups within the compounds of the invention, or phosphate esters of the compounds of the invention.
  • solvate refers to the physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association often includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, and methanolates.
  • N-protecting group or “N-protected” refers to those groups capable of protecting an amino group against undesirable reactions. Commonly used N-protecting groups are described in Greene and Wuts, PROTECTING GROUPS IN CHEMICAL SYNTHESIS (3 rd ed., John Wiley & Sons, NY (1999).
  • N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, or 4-nitrobenzoyl; sulfonyl groups such as benzenesulfonyl or p-toluenesulfonyl; sulfenyl groups such as phenylsulfenyl (phenyl-S-) or triphenylmethylsulfenyl (trityl-S-); sulfinyl groups such as p-methylphenylsulfinyl (p- methylphenyl-S(O)-)
  • N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • the compounds of the present invention can be prepared using a variety of methods.
  • Formula V (3 ⁇ 4 can be, for example, O or NR A , where R A is as described hereinabove and is preferably H or R E as defined above such as Cl- C6alkyl, 3- to 12-membered carbocycle or heterocycle, -C(0)R s , -C(0)OR s , -C(0)N(R s R s '), - S0 2 N(R s R s '), -S(0) 2 OR s , -S(0)OR s , -S(0)N(R s R s '), or a suitable protecting group such as Boc or Fmoc), or Formula VIII (E can be, for example, 3- to 7-membered carbocycle or heterocycle and is optionally substituted with one or more R A ),
  • the 1,4-diketones II, V, and VIII can be reduced to the 1,4-diols using the methods described below, and the resultant racemic, enantiomerically enriched, or meso 1,4-diols may be converted to the dimesylates III, VI, or IX, or alternatively to ditriflates, ditosylates, or dihalides by the methods described below.
  • the dimesylates III, VI, and IX, ditriflates, ditosylates, or dihalides may be reacted with an amine, including but not limited to, aniline, 3,5-difluoroaniline, 3,4-difluoroaniline, 4- fluoroaniline, 3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroaryl amines, alkyl amines, cycloalkyl amines, substituted benzylamines, or allylamine, under the conditions described below to give the compounds of the invention.
  • Li and L 2 can be readily introduced to Formulae II, V and VIII, as appreciated by those skilled in the art in light of the present invention.
  • D-L 3 - NH 2 can be used instead of D-NH 2 , as appreciated by those skilled in the art.
  • the compounds of the present invention can be prepared starting from compounds of Formula II and Formula III as shown in Scheme II.
  • the 1,4-diketones such as Formula IV may be prepared using known methods (see Nevar, et al., Synthesis: 1259-1262 (2000), such as the reaction of a-bromoketones such as Formula II with methyl ketones such as Formula III in the presence of a suitable Lewis acid such as ZnCl 2 or Ti(OiPr) 4 .
  • reaction of II (1 equivalent) with III (1.5 equivalents) in the presence of ZnC3 ⁇ 4 (2 equivalents), diethylamine (1.5 equivalents) and teri-butanol (1.5 equivalents) in a solvent such as benzene at around room temperature can provide the diketones IV.
  • the 1,4-diketones IV may be reduced to the 1 ,4-diols such as V by the action of NaBH 4 , LiAlH 4 , or DIBAL.
  • enantioselective reduction of 1 ,4- diketones such as Formula IV can be accomplished by analogy with reported methods (see Chong, et al., Tetrahedron: Asymmetry 6:409-418 (1995), Li, et al., Tetrahedron 63 :8046-8053 (2007), Aldous, et al., Tetrahedron: Asymmetry 1 1 :2455-2462 (2000), Masui, et al., Synlett:273-274 (1997), Jing, et al., Adv. Synth. Catal.
  • the diketones IV (1 equivalent) can be reduced by NaBH4 (3 equivalents) in solvents such as tetrahydrofuran with heating to about 50 °C.
  • the diketones IV (1 equivalent) can be enantioselectively reduced upon addition to a mixture made from AyV-diethylaniline borane (about 2 equivalents), trimethylborate (about 0.2 equivalents) and either (S) or (R) a,a-diphenyl-2-pyrrolidinemethanol (about 0.17 equivalents) in a solvent such as THF at temperatures ranging from about 10 °C to about 30 °C (Synthesis 2507-2510 (2003)).
  • the resultant racemic, enantiomerically enriched, or meso 1 ,4-diols V may be reacted with methanesulfonyl chloride or methanesulfonic anhydride to provide the dimesylate Formula VI.
  • diols V (1 equivalent) can be reacted with methanesulfonic anhydride (about 2.5 equivalents) in the presence of a base such as diisopropylethylamine (about 4 equivalents) in a solvent such as tetrahydrofuran or 2-methyltetrahydrofuran at temperatures starting from about -15 °C to -25 °C and increasing to about room temperature.
  • Formula V may be converted to a ditriflate or ditosylate by the action of p-toluenesulfonyl chloride or triflic anhydride, or to a dihalide such as a dibromide or dichloride by the action of PPh 3 in the presence of CC or CBr 4 , or by the action of SOCI 2 , POCI 3 , or PBr 3 .
  • the dimesylate, ditriflate, ditosylate, or dihalide may be reacted with an amine, such as 4- fluoroaniline (as shown for illustration in Scheme II), with or without a co-solvent such as DMF at room temperature to 100 °C, to give the pyrrolidines such as Formula VII.
  • an amine such as 4- fluoroaniline (as shown for illustration in Scheme II)
  • a co-solvent such as DMF at room temperature to 100 °C
  • the dimesylate VI (1 equivalent) (or in the alternative the ditriflate, ditosylate, or dihalide) may be reacted with between 1 to 20 equiv of an amine D-NH2, such as, for example, a substituted aniline in solvents such as tetrahydrofuran or 2-methyltetrahydrofuran with or without a co-solvent such as DMF, at about room temperature to about 100 °C, to give the pyrrolidines such as Formula VII.
  • amine D-NH 2 such as, for example, a substituted aniline in solvents such as tetrahydrofuran or 2-methyltetrahydrofuran with or without a co-solvent such as DMF
  • a base such as diisopropylethylamine can be added to promote the reaction.
  • the amine can be used in a large excess (i.e., as reaction solvent).
  • reaction solvent i.e., as reaction solvent
  • the reaction of a dimesylate (1 equivalent) with excess aniline (about 6.5 equivalents) can be conducted by heating to 65 °C in 2-methyltetrahydrofuran until completion of the reaction.
  • the dinitro Formula VII may be reduced to the diamino Formula VIII using Fe in the presence of NH 4 C1, HC1, or acetic acid, or by treatment with a hydride reducing agent, such as sodium borohydride (with or without the addition of a transition metal salt, such as B1CI3, SbC3 ⁇ 4, NiC3 ⁇ 4, CU2CI2, or C0CI2) in a solvent such as ethanol or THF.
  • a hydride reducing agent such as sodium borohydride (with or without the addition of a transition metal salt, such as B1CI3, SbC3 ⁇ 4, NiC3 ⁇ 4, CU2CI2, or C0CI2) in a solvent such as ethanol or THF.
  • a hydride reducing agent such as sodium borohydride (with or without the addition of a transition metal salt, such as B1CI3, SbC3 ⁇ 4, NiC3 ⁇ 4, CU2CI2, or C0CI2
  • compounds VII (1 equivalent) can be reduced to VIII by reaction with iron powder (about 6
  • Formula VII can be reduced to the product Formula VIII by hydrogenation in the presence of a suitable catalyst, such as a palladium or platinum catalyst or Raney-nickel.
  • a suitable catalyst such as a palladium or platinum catalyst or Raney-nickel.
  • reduction of VII to VIII can be effected by exposure to 30 psig hydrogen gas in the presence of Raney-nickel Grace 2800 in a solvent such as tetrahydrofuran with shaking.
  • the diamine Formula VIII may be reacted with a suitably protected proline acid (Boc is shown, although Cbz, Troc, or Fmoc may be substituted) in the presence of a peptide coupling reagent, such as EDAC/HOBT, PyBOP, HATU, T3P or DEPBT, in a solvent such as THF, DMF, dichloromethane, ethyl acetate, or DMSO, with or without the addition of an amine base such as /V-methylmorpholine, Hunig's base, pyridine, 2,6-lutidine, or triethylamine, to give Formula IX.
  • a peptide coupling reagent such as EDAC/HOBT, PyBOP, HATU, T3P or DEPBT
  • a solvent such as THF, DMF, dichloromethane, ethyl acetate, or DMSO
  • an amine base such as /V-methylmorpholine, Hunig'
  • reaction of VIII (1 equivalent) with l-(teri-butoxycarbonyl)pyrrolidine-2- carboxylic acid (2.5 equivalents) and HATU (2.5 equivalents) in the presence of diisopropylethylamine (3 equivalents) in DMSO at about room temperature can provide the product IX.
  • Removal of the Boc protecting groups to give X may be accomplished by treatment with an acid, such as TFA, HC1, or formic acid.
  • reaction of IX (1 equivalent) with TFA:CH 2 Cl2 (1 :1) at room temperature can provide compounds X.
  • Compounds XI may be prepared by coupling of Formula X with an acid of choice using the standard peptide coupling reagents and conditions described above.
  • X(l equivalent) can be reacted with acids (2 equivalents) such as, but not limited to, 2-(methoxycarbonylamino)-3-methylbutanoic acid, 2-(methoxycarbonylamino)-3,3- dimethylbutanoic acid, 2-cyclohexyl-2-(methoxycarbonylamino)acetic acid, 2- (methoxycarbonylamino)-2-(tetrahydro-2i7-pyran-4-yl)acetic acid, or acids listed under General Procedure 19.
  • acids (2 equivalents) such as, but not limited to, 2-(methoxycarbonylamino)-3-methylbutanoic acid, 2-(methoxycarbonylamino)-3,3- dimethylbutanoic acid, 2-cyclohexyl-2-(methoxycarbonylamino)acetic acid, 2- (methoxycarbonylamino)-2-(tetrahydro-2i7-pyran-4-yl)acetic acid, or acids listed under General Procedure 19.
  • diamine VIII may be reacted directly with an appropriately /V-substituted proline in the presence of a peptide coupling reagent such as EDAC/HOBT, PyBOP, HATU, T3P, or DEPBT, in a solvent such as THF, DMF, dichloromethane, or DMSO, with or without the addition of an amine base such as /V-methylmorpholine, Hunig's base, pyridine, 2,6-lutidine, or triethylamine, to directly give compounds XI.
  • a peptide coupling reagent such as EDAC/HOBT, PyBOP, HATU, T3P, or DEPBT
  • a solvent such as THF, DMF, dichloromethane, or DMSO
  • an amine base such as /V-methylmorpholine, Hunig's base, pyridine, 2,6-lutidine, or triethylamine
  • VIII (1 equivalent) can be reacted directly with l-(2- (methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid (about 2 equivalents) and T3P (about 2.8 equivalents) in the presence of diisopropylethylamine (about 5.5 equivalents) in a solvent such as ethyl acetate at temperatures from about 0 °C to about room temperature to provide XI.
  • a solvent such as ethyl acetate
  • the compounds of the present invention can be prepared starting from compounds of Formula II and Formula III as shown in Scheme III, where A, B, D, Y, and Z are as described above, using conditions similar to those described above for the preparation of IV in Scheme II.
  • the resulting 1,4-diketone IV may be reduced to the 1,4-diols V using the methods described above for Scheme II.
  • the resultant racemic, enantiomerically enriched, or meso 1,4-diols V may be converted to the dimesylate VI or alternatively to a ditriflate, ditosylate, or dihalide by the methods described above.
  • the dimesylate VI, ditriflate, ditosylate, or dihalide may be reacted with an amine, including but not limited to, aniline, 3,5-difluoroaniline, 3,4-difluoroaniline, 4- fluoroaniline, 3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroaryl amines, alkyl amines, cycloalkyl amines, substituted benzylamines, or allylamine, under the conditions described above the give the compounds of the invention.
  • an amine including but not limited to, aniline, 3,5-difluoroaniline, 3,4-difluoroaniline, 4- fluoroaniline, 3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroaryl amines, alkyl amines, cycloalkyl amines, substituted benzylamines, or allylamine, under the conditions described above the
  • Amine IX may be reacted with an aryl halide or triflate such as X (iodide shown for illustration) employing the Buchwald- Hartwig reaction in the presence of a palladium catalyst (such as Pd(OAc)2 or Pd2(dba) 3 ) and a phosphine ligand (such as triphenylphosphine or XantPhos) and a base (such as sodium bis(trimethylsilyl)amide, potassium tert-butoxide, or K 3 P0 4 ) to give the compounds of the present invention.
  • a palladium catalyst such as Pd(OAc)2 or Pd2(dba) 3
  • a phosphine ligand such as triphenylphosphine or XantPhos
  • a base such as sodium bis(trimethylsilyl)amide, potassium tert-butoxide, or K 3 P0 4
  • the compounds of the present invention may be obtained by reaction of IX with an aldehyde or ketone through reductive amination in the presence of a hydride reducing agent, such as sodium borohydride or sodium cyanoborohydride (with or without the addition of an acid, such as acetic acid) in a solvent such as ethanol, toluene, THF, or dichloromethane.
  • a hydride reducing agent such as sodium borohydride or sodium cyanoborohydride (with or without the addition of an acid, such as acetic acid) in a solvent such as ethanol, toluene, THF, or dichloromethane.
  • a suitable catalyst such as a palladium or platinum catalyst or Raney nickel.
  • amine IX may react with electrophilic reagents, such as alkyl halides, or with aryl electrophiles (suitably electron deficient aryl and heteroaryl halides and triflates) through nucleophilic aromatic substitution reactions to give the compounds of the present invention.
  • electrophilic reagents such as alkyl halides, or with aryl electrophiles (suitably electron deficient aryl and heteroaryl halides and triflates) through nucleophilic aromatic substitution reactions to give the compounds of the present invention.
  • R allyl or substitued benzyl
  • the compounds of XIII can be prepared starting from compounds of Formula II and Formula III as shown in Scheme IV, where X 5 in Formula II and Formula III represents a halogen (e.g., CI, Br, or F) or a nitro group. Additionally, each phenyl ring can be substituted with Xi 3 , wherein X13 is X5, H, alkyl, haloalkyl, alkoxy, or haloalkoxy.
  • the 1 ,4- diketones such as IV may be prepared using known methods described above for the preparation of IV for Scheme II.
  • the 1,4-diketones IV may be reduced to the 1 ,4-diols such as V by the action of NaBH 4 , L1AIH 4 , or DIBAL.
  • enantioselective reduction of 1,4-diketone such as IV can be accomplished by the methods described above for the preparation of V in Scheme II.
  • the chiral reduction may proceed with lower stereoselectivity with an additional substituent X13 on the phenyl ring.
  • the resultant racemic, enantiomerically enriched, or meso 1 ,4- diols V may be reacted with methansulfonyl chloride or methanesulfonic anhydride to provide the dimesylate VI.
  • Alternatively V may be converted to a ditriflate or ditosylate by the methods described above for Scheme II.
  • the dimesylate, ditriflate, ditosylate, or dihalide may be reacted, analogously to Scheme II, with an amine D-NH 2 including but not limited to those amines described or referred to in Scheme II to give VII.
  • the nitro groups may be reduced to the tetraamino product IX using Fe in the presence of NH 4 C1, HC1, or acetic acid, or with a hydride reducing agent, such as sodium borohydride (with or without the addition of a transition metal salt, such as B1CI 3 , SbCl 3 , NiCl 2 , Cu 2 Cl 2 , or CoCl 2 ) in a solvent such as ethanol or THF.
  • a hydride reducing agent such as sodium borohydride (with or without the addition of a transition metal salt, such as B1CI 3 , SbCl 3 , NiCl 2 , Cu 2 Cl 2 , or CoCl 2 ) in a solvent such as ethanol or THF.
  • a suitable catalyst such as a palladium or platinum catalyst or Raney nickel.
  • Formula IX may be reacted with a suitably protected proline acid (Boc is shown, although Cbz, Troc, or Fmoc may be substituted) in the presence of a peptide coupling reagent, such as EDAC/HOBT, PyBOP, HATU, T3P, or DEPBT, in a solvent such as THF, DMF, dichloromethane, or DMSO, with or without the addition of an amine base, such as N- methylmorpholine, Hunig's base, pyridine, 2,6-lutidine, or triethylamine, to give X as a mixture of the amide products.
  • a peptide coupling reagent such as EDAC/HOBT, PyBOP, HATU, T3P, or DEPBT
  • a solvent such as THF, DMF, dichloromethane, or DMSO
  • an amine base such as N- methylmorpholine, Hunig's base, pyridine, 2,6-luti
  • formula X depicts reaction taking place on a specific NH 2 group, the reaction may take place at either NH 2 .
  • Conversion to the benzimidazole compound XI may be accomplished by heating X in acetic acid (50-100 °C).
  • XI may be prepared by reaction of IX with an aldehyde, followed by treatment with an oxidant, such as Cu(OAc) 2 or Mn0 2 (see Penning, et al., Bioorg. Med. Chem. 2008, 16, 6965-6975.
  • the compounds of the present invention may be prepared by coupling of the resulting diamine XII with an acid of choice using the standard peptide coupling reagents and conditions described above for
  • IX in Scheme IV may be prepared from a compound of Formula II as shown in Scheme V.
  • Compound VIII from Scheme II may be treated with an acylating agent such as acetyl chloride or acetic anhydride to give compound II (Scheme V).
  • Nitration of compound II to provide III may be accomplished using known methods, such as treatment with nitric acid or potassium nitrate in the presence of an acid such as sulfuric acid or treatment with NO 2 BF 4 .
  • Removal of the acetamide protecting group may be accomplished by treatment with Boc anhydride in the presence of DMAP to give IV, followed by sequential treatment of IV with hydroxide (such as NaOH, KOH, or LiOH) to remove the acetyl group and a strong acid such as TFA or HC1 to remove the Boc protecting group to provide V.
  • hydroxide such as NaOH, KOH, or LiOH
  • the compounds of the present invention can be prepared starting from compounds of Formula II as shown in Scheme VI, where A, B, D, Y, and Z are as described above.
  • a 1,4-diketone compound of Formula II (prepared as described in Scheme III) may be reacted with an amine, including but not limited to, aniline, 3,5-difluoroaniline, 3,4- difluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroaryl amines, alkyl amines, cycloalkyl amines, substituted benzylamines, or allylamine, under acid catalyzed conditions, such as acetic acid, TFA, formic acid or HC1, to give the compounds of the invention.
  • the compounds of the present invention can be prepared from a compound of Formula II as shown in Scheme VII.
  • a compound of Formula II, where R x is a halogen, such as bromo, chloro, or iodo, or a triflate or a nonaflate may be converted to a boronic acid or ester such as Formula III, using the chemistry analogous to that of Scheme II to prepare VII (in Scheme II); for example, by starting with l-(4-bromophenyl)ethanone and 2-bromo-l-(4- bromophenyl)ethanone.
  • a compound of Formula II, where R x is a halogen, such as bromo, chloro, or iodo, or a triflate or a nonaflate may be converted to a boronic acid or ester such as Formula III, (e.g., a cyclic pinacolate ester) where R is hydrogen, methyl, ethyl, or a cyclic pinacolate ester.
  • a boronic acid or ester such as Formula III, (e.g., a cyclic pinacolate ester) where R is hydrogen, methyl, ethyl, or a cyclic pinacolate ester.
  • a compound of Formula II can be transformed to a compound of III by treatment with pinacol-borane in the presence of a catalyst such as, for example, tris(dibenzylidineacetone)palladium (0), and a ligand such as, for example, tri-t-butylphosphine, in solvents such as, for example, tetrahydrofuran, dioxane, or toluene at temperatures ranging from ambient to about 130°C.
  • a catalyst such as, for example, tris(dibenzylidineacetone)palladium (0)
  • a ligand such as, for example, tri-t-butylphosphine
  • solvents such as, for example, tetrahydrofuran, dioxane, or toluene at temperatures ranging from ambient to about 130°C.
  • compound II can be reacted with bis(pinacolato)diboron in the presence of a catalyst such as, for example, Combipho
  • a ligand such as, for example, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos)
  • XPhos 2-dicyclohexylphosphino-2',4',6'-triisopropyl
  • a compound of Formula II may be reacted with an organolithium reagent, such an n-BuLi, sec-BuLi, or t-BuLi, followed by reaction with trimethyl borate or triethyl borate, to give a compound of Formula III.
  • organolithium reagent such as n-BuLi, sec-BuLi, or t-BuLi
  • a compound of Formula III in Scheme VII can be coupled with a compound of Formula IV, where R Y is a halogen, such as bromo, chloro or iodo, under Suzuki reaction conditions to provide a compound of Formula V.
  • a palladium catalyst such as, for example, tris(dibenzylidineacetone)palladium (0), palladium acetate, bis(triphenylphosphine)palladium (II) chloride, tetrakis(triphenylphosphine)palladium, or dichloro[l,l'-bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct; base such as, for example, potassium carbonate, potassium phosphate, potassium t-butoxide, sodium carbonate, cesium carbonate, or cesium fluoride; and solvent such as, for example, toluene, ethanol, water, or tetrahydrofur
  • Removal of the Boc protecting groups from V may be accomplished by treatment with an acid, such as TFA, HCl, or formic acid.
  • Certain compounds of the present invention such as VI may be prepared by coupling the resulting amino compounds with an acid of choice using the standard peptide coupling reagents, such as EDAC/HOBT, PyBOP, HATU, or DEPBT, in a solvent such as THF, DMF, dichloromethane, or DMSO, with or without the addition of an amine base such as N- methymorpholine, Hunig's base, pyridine, 2,6-lutidine, or triethylamine.
  • Each R z is independently - L Y '-M'-R D (e.g., -L Y -N(RB")C(0)-L S -R e ), and D, L 3 , 3 ⁇ 4, R 2 , R 5 , , RB", L S , R E , L Y ', M' and R D are as defined above.
  • the functionality of T-R D can similarly be introduced following removal of the Boc protecting groups in V give compounds of Formula VII.
  • Scheme VII As another non-limiting example, the compounds of the present invention can be prepared according to Scheme VIII starting from the compound of Formula II, initially cleaving the diol in oxidative fashion followed by subsequent acid hydrolysis of the acetonide. This dialdehyde intermediate is then treated with an aryl boronate or aryl boronic acid (compound IV where A and Y are as described previously, or compound VII) and aniline III (where W is R M or J, and R M and J are as defined above) resulting in the formation of Formula V or Formula VIII respectively.
  • aryl boronate or aryl boronic acid compound IV where A and Y are as described previously, or compound VII
  • aniline III where W is R M or J, and R M and J are as defined above
  • Formula V can be derivatized by deprotonating the hydroxyl groups with a strong base such as sodium hydride, butyl lithium, or potassium hydride, followed by alkylation with R s -halogen.
  • a strong base e.g., sodium hydride
  • R s -halogen alkylation with R s -halogen as well, followed by acid hydrolysis of the phenol protecting groups.
  • the sulfonylation of the phenols with nonafluorobutylsulfonyl fluoride in the presence of a neutralizing agent such as potassium carbonate in a polar aprotic solvent such as DMF, followed by heating provides a compound of Formula IX.
  • Boronate of Formula X is produced by heating Formula IX with bis(pinacolato)diboron in the presence of X-phos and a palladium catalyst, such as Pd2(dba)3 and a base such as potassium acetate in an organic solvent such as dioxane.
  • Formula X is further derivatized to final product by heating a suitably substituted heteroarylhalide in the presence of a palladium catalyst such as PdC12(dppf) in the presence of a base such as sodium carbonate in a mixture of toluene and ethanol.
  • the compounds of the present invention can be prepared according to Scheme IX starting from the compounds of Formula II and Formula III.
  • Formula III carboxylic acid is activated towards coupling using reagents such as isobutylchloroformate, DCC, EDAC, or HATU in the presence of an organic base, such as diisopropylethylamine.
  • reagents such as isobutylchloroformate, DCC, EDAC, or HATU
  • an organic base such as diisopropylethylamine.
  • dianiline of Formula II is added to the reaction, with the isolation of an intermediate amide, which is heated in acetic acid, preferably at 60 °C, to yield the compound of Formula IV.
  • the benzimidazole of Formula IV is treated with SEM-C1 in the presence of a base in an aprotic solvent such as THF, yielding two protected benzimidazole regioisomers V.
  • the boronate esters VI are produced by heating Formula V with bis(pinacolato)diboron in the presence of a palladium catalyst, such as PdC12(dppf), X-Phos, and a base such as potassium acetate in an organic solvent such as dioxane. Heating yields both benzimidazole regioisomers VI.
  • Diol VII is cleaved in oxidative fashion followed by subsequent acid hydrolysis of the acetonide.
  • This dialdehyde intermediate is then treated with an aryl boronate VI and aniline VIII (where W is R M or J, and R M and J are as defined above) resulting in the formation of the 3 benzimidazole regioisomers of Formula IX.
  • Formula X is produced by deprotonating the hydroxyl groups with a strong base such as sodium hydride, butyl lithium, or potassium hydride, followed by alkylation with R s -halogen, followed by acid hydrolysis of the pyrrolidine and benzimidazole protecting groups, preferably by treatment with mineral acid, such as hydrochloric acid in an alcoholic solvent such as methanol.
  • the carboxylic acid R Z -COOH is activated towards coupling using reagents such as isobutylchloroformate, DCC, EDAC, or HATU in the presence of an organic base, such as diisopropylethylamine.
  • reagents such as isobutylchloroformate, DCC, EDAC, or HATU
  • organic base such as diisopropylethylamine.
  • the diketone (3) can be converted to the bisboronate (4) by reaction with bis(pinacolato)diborane in the presence of a base such as potassium acetate, a catalyst such as PdCl 2 (dppf)-CH 2 Cl 2 , in a solvent such as DMSO, dimethoxyethane or dioxane with heating to between 60-100 °C.
  • Bisboronate (4) can be converted to the intermediate (5) by Suzuki reaction using, in analogous fashion, the Suzuki conditions described in Scheme VII.
  • the intermediate (5) can be converted to (6) by reaction with an amine D-NH 2 under the analogous conditions described in Scheme VI.
  • reaction of (5) with D-NH 2 in the presence of an acid such as, but not limited to, TFA, in a solvent such as, but not limited to, toluene and with heating up to 110 °C can provide intermediates of general structure (6).
  • Compounds (6) can be converted to compounds of general formulas (7) and then (8) using, in analogous fashion, the methods described in Scheme VII.
  • the functionality of T-R D can be similarly introduced to compounds of Formula (7) to give compounds of Formula (X-l).
  • the intermediates (6) can also be prepared using the route depicted in Scheme XI.
  • the intermediate (3) can be reacted with an amine D-NH 2 using, in analogous fashion, the conditions described in Schemes VI and X to provide intermediates (9), which can be converted to (10) using, analogously, conditions as described above in Scheme X; and (10),in turn, can be converted to compounds (6) using the Suzuki reaction conditions described in Scheme VII.
  • the compounds of the invention of general formula (15), where R 2 o is -L S '-M'-L S "-R D and D is as described above can be prepared as shown in Scheme XII.
  • a 1 ,4-diketone compound (3) may be reacted with an amine D-NH 2 , under acid catalyzed conditions, such as acetic acid, TFA, formic acid or HC1, to give the compounds (11).
  • a diketone (3) (1 equivalent) can be reacted with an aniline (1.2 equivalents) and TFA (2 equivalents) in a solvent such as toluene with heating to between around 80 and 120 °C to provide the compounds (11).
  • a diketone (3) can be reacted with an aniline (about 10 equivalents) with heating in acetic acid to around about 70 °C to provide the compounds (11).
  • Amines that can be reacted according to the foregoing description include but are not limited to, those amines described or referred to in Scheme II as suitable for reacting with intermediate (5).
  • Compounds of formula (11) can be converted to compounds of formula (12) by reduction with iron in the presence of ammonium chloride.
  • reaction of compounds (11) (1 equivalent) with iron powder (about 6 equivalents) in the presence of ammonium chloride (about 3 equivalents) in a mixed solvent of ethanohTHF: water (1 :1 :0.25) at reflux can provide compounds (12).
  • the conversion of (11) to (12) may also be effected by other methods described above in Scheme II to convert VII to VIII, for example by catalytic hydrogenation.
  • Compounds (12) (1 equivalent) can be converted to compounds (13) using the peptide coupling condition described for the conversion of VIII to IX in Scheme II, for example using EDAC/HOBt (2 equivalents) and an appropriate acid in solvents such as DMF at around room temperature.
  • Compounds (13) can be converted to compounds (14) using TFA/CH 2 CI 2 as described above for converting IX to X in Scheme II.
  • Compounds (14) can be converted to compounds (15) using procedures analogous to those in Scheme II to convert X to XI, such as the coupling procedure to convert (12) to (13).
  • the functionality of T-R D can be similarly introduced to compounds of Formula (14) to give compounds of Formula (XII- 1).
  • This Buchwald reaction can be conducted in the presence of a base (e.g., cesium carbonate), a palladium catalyst (e.g., tris(dibenzylideneacetone)dipalladium(0)), a phosphine ligand (e.g., 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) in solvent such as dioxane with heating to about 80-120 °C.
  • a base e.g., cesium carbonate
  • a palladium catalyst e.g., tris(dibenzylideneacetone)dipalladium(0)
  • a phosphine ligand e.g., 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
  • Each phenyl ring in the above structures can be substituted with X 13 , wherein X 13 is H, halogen, alkyl, haloalkyl, alkoxy, or haloalkoxy.
  • X 13 is H, halogen, alkyl, haloalkyl, alkoxy, or haloalkoxy.
  • Certain compounds of the invention of general formula (29), where R20 is -L S '-M'-L S "-R D and D is as described above, can be prepared according to the methods of Scheme XV.
  • Compounds of formula (24) can be converted to compounds of formula (25) (Sonogashira reaction) by reaction with trimethylsilylacetylene, a palladium catalyst (e.g., bis(triphenylphosphine)palladium(II)chloride), a copper catalyst (e.g., copper(I)iodide), and a base (e.g., triethylamine) wherein an amine base can also be used as solvent.
  • a palladium catalyst e.g., bis(triphenylphosphine)palladium(II)chloride
  • a copper catalyst e.g., copper(I)iodide
  • a base e.g., triethylamine
  • the compounds (25) can be desilylated to compounds (26) by reaction with a fluoride source (e.g., tetrabutylammonium fluoride) in a solvent such as THF.
  • a fluoride source e.g., tetrabutylammonium fluoride
  • Compounds (26) can be converted to compounds (27) by formation of the dianion of (26) with n-butyllithium and subsequent reaction with a Weinreb amide (e.g., N-(tert-butoxycarbonyl)-L-proline-N'-methoxy- N'methylamide). This reaction can be conducted in an appropriate solvent such as THF or dimethoxy ethane.
  • Compounds (27) can be converted to compounds (28) by reaction with hydrazine in a solvent such as ethanol.
  • the compounds (28) can be converted to compounds (29) using the methods described generally in the foregoing Schemes.
  • the functionality of T-R D can be similarly introduced to
  • Certain compounds of the invention of general formula (34), where R 20 is -L S '-M'-L S "-RD and D is as described above, can be prepared according to the methods of Scheme XVI.
  • Compounds (24) can be converted to compounds (30) by reaction of (24) with CO(g) under pressure (ca. 60 psi) in the presence of a palladium catalyst (e.g., PdCl 2 (dppf)) in methanol as solvent and with heating to around 100 °C.
  • a palladium catalyst e.g., PdCl 2 (dppf)
  • Compounds (30) can be converted to compounds (31) by reaction with hydrazine in a solvent such as methanol with heating to about 60-80 °C.
  • Compounds (31) can be converted to compounds (32) by reaction withN-Boc-2-cyano-pyrrolidine in the presence of a base (e.g., potassium carbonate) in a solvent such as butanol and with heating to around 150 °C with irradiation in a microwave reactor.
  • a base e.g., potassium carbonate
  • Compounds (32) can be deprotected to compounds (33) and acylated to (34) using, in analogous fashion, the conditions described generally in the foregoing Schemes.
  • T-R D can be similarly introduced to compounds of Formula (33) to give compounds of Formula (XVI- 1).
  • Certain compounds of the invention of general formula (38), where R 2 o is -L S '-M'-L S "-R D and D is as described above, can be prepared according to the methods of Scheme XVII.
  • Compounds of formula (24) can be converted to compounds (35) by reaction with CuCN in a solvent such as DMF and with heating to about 160 °C with microwave irradiation.
  • Compounds (35) can be converted to compounds (36) by reaction with HCl(g) in anhydrous methanol at 0 °C with warming to room temperature.
  • Compounds (36) can be converted to compounds (37) by reaction with NH 3 (g) in anhydrous methanol at 0 °C with warming to room temperature.
  • Compounds (37) can be converted to compounds (38) by reaction with (41) in THF in the presence of a base (e.g., potassium carbonate).
  • a base e.g., potassium carbonate
  • the functionality of T-R D can be similarly introduced to compounds of Formula (33) to give compounds of Formula (XVII- 1).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Oncology (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
PCT/US2012/026456 2011-02-25 2012-02-24 Anti-viral compounds WO2012116257A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
ES12716757.5T ES2624246T3 (es) 2011-02-25 2012-02-24 Compuestos antivirales
MX2013009763A MX346264B (es) 2011-02-25 2012-02-24 Compuestos antivirales.
CN201280020257.2A CN103596941B (zh) 2011-02-25 2012-02-24 抗病毒化合物
CA2828495A CA2828495A1 (en) 2011-02-25 2012-02-24 Anti-viral compounds
JP2013555589A JP2014510063A (ja) 2011-02-25 2012-02-24 抗ウイルス性化合物
EP12716757.5A EP2678334B1 (en) 2011-02-25 2012-02-24 Anti-viral compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161446800P 2011-02-25 2011-02-25
US61/446,800 2011-02-25

Publications (1)

Publication Number Publication Date
WO2012116257A1 true WO2012116257A1 (en) 2012-08-30

Family

ID=46001714

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2012/026456 WO2012116257A1 (en) 2011-02-25 2012-02-24 Anti-viral compounds

Country Status (10)

Country Link
US (2) US9394279B2 (zh)
EP (1) EP2678334B1 (zh)
JP (1) JP2014510063A (zh)
CN (1) CN103596941B (zh)
CA (1) CA2828495A1 (zh)
ES (1) ES2624246T3 (zh)
HU (1) HUS1700040I1 (zh)
MX (1) MX346264B (zh)
TW (1) TWI586660B (zh)
WO (1) WO2012116257A1 (zh)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015528511A (ja) * 2012-09-18 2015-09-28 アッヴィ・インコーポレイテッド C型肝炎を治療するための方法
US9326973B2 (en) 2012-01-13 2016-05-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9333204B2 (en) 2014-01-03 2016-05-10 Abbvie Inc. Solid antiviral dosage forms
JP2016513695A (ja) * 2013-03-14 2016-05-16 アッヴィ・インコーポレイテッド C型肝炎を治療するための2種の抗ウイルス剤の併用
US9340520B2 (en) 2011-02-07 2016-05-17 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9546160B2 (en) 2011-05-12 2017-01-17 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9717712B2 (en) 2013-07-02 2017-08-01 Bristol-Myers Squibb Company Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis C virus
US9770439B2 (en) 2013-07-02 2017-09-26 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9775831B2 (en) 2013-07-17 2017-10-03 Bristol-Myers Squibb Company Combinations comprising biphenyl derivatives for use in the treatment of HCV
US10201541B1 (en) 2011-05-17 2019-02-12 Abbvie Inc. Compositions and methods for treating HCV
US10286029B2 (en) 2013-03-14 2019-05-14 Abbvie Inc. Method for treating HCV
US10617675B2 (en) 2015-08-06 2020-04-14 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
JP2020059696A (ja) * 2010-10-13 2020-04-16 アッヴィ・アイルランド・アンリミテッド・カンパニー 抗ウィルス化合物
US10730874B2 (en) 2018-03-13 2020-08-04 Shire Human Genetic Therapies, Inc. Inhibitors of plasma kallikrein and uses thereof
US11370803B2 (en) 2019-09-18 2022-06-28 Takeda Pharmaceutical Company Limited Heteroaryl plasma kallikrein inhibitors
US11484534B2 (en) 2013-03-14 2022-11-01 Abbvie Inc. Methods for treating HCV
US11787796B2 (en) 2019-09-18 2023-10-17 Takeda Pharmaceutical Company Limited Plasma Kallikrein inhibitors and uses thereof

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102245604A (zh) 2008-12-23 2011-11-16 雅培制药有限公司 抗病毒化合物
CN102264737A (zh) 2008-12-23 2011-11-30 雅培制药有限公司 抗病毒化合物
EP2419404B1 (en) * 2009-04-15 2015-11-04 AbbVie Inc. Anti-viral compounds
NZ591973A (en) 2009-06-11 2013-03-28 Abbott Lab Anti-viral compounds to treat hcv infection
US8937150B2 (en) 2009-06-11 2015-01-20 Abbvie Inc. Anti-viral compounds
NZ605440A (en) 2010-06-10 2014-05-30 Abbvie Bahamas Ltd Solid compositions comprising an hcv inhibitor
US9034832B2 (en) * 2011-12-29 2015-05-19 Abbvie Inc. Solid compositions
CN108187056A (zh) 2013-03-14 2018-06-22 艾伯维公司 用于治疗hcv患者的直接作用的抗病毒剂和利巴韦林的组合
PL3043803T3 (pl) 2013-09-11 2022-11-07 Emory University Kompozycje nukleotydowe i nukleozydowe oraz ich zastosowanie
AU2015240753B2 (en) * 2014-04-02 2020-01-16 Abbvie Inc. Methods for treating HCV
WO2016134058A1 (en) 2015-02-18 2016-08-25 Abbvie Inc. Combinations useful to treat hepatitis c virus
US20160375017A1 (en) 2015-06-26 2016-12-29 Abbvie Inc. Solid Pharmaceutical Compositions for Treating HCV
SG10202002899VA (en) 2015-06-26 2020-05-28 Abbvie Inc Solid pharmaceutical compositions for treating hcv
BR112018000383A2 (pt) 2015-07-08 2018-09-18 Abbvie Inc métodos para tratar hcv
SG10202002900YA (en) 2015-07-17 2020-05-28 Abbvie Inc Solid pharmaceutical compositions for treating hcv
WO2017189978A1 (en) 2016-04-28 2017-11-02 Emory University Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto
JP2018131439A (ja) 2017-02-14 2018-08-23 アッヴィ・インコーポレイテッド Hcvを処置する方法
CA2981993A1 (en) 2017-08-02 2019-02-02 Abbvie Inc. Methods for treating hcv
EP3694512A1 (en) 2017-10-12 2020-08-19 Abbvie Inc. Methods for treating hcv
EP3843712A4 (en) * 2018-08-29 2022-08-17 Abbvie Inc. METHOD FOR MANUFACTURING ACTIVE DRUG SUBSTANCE OF PIBRENTASVIR
EP3952838A1 (en) 2019-04-08 2022-02-16 Abbvie Inc. Solid pharmaceutical compositions for treating hcv
CN111072513B (zh) * 2019-12-30 2022-03-08 苏州敬业医药化工有限公司 一种肝炎药物中间体的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5095153A (en) 1988-09-30 1992-03-10 Himont Incorporated Diethers usable in the preparation of ziegler-natta catalysts
US20090076076A1 (en) 2007-06-13 2009-03-19 Baylor University Inhibitors of cysteine proteases and methods of use thereof
WO2010144646A2 (en) * 2009-06-11 2010-12-16 Abbott Laboratories Anti-viral compounds

Family Cites Families (156)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD75755A (zh)
DE75755C (de) 1894-06-14 DAHL & COMP, in Barmen Verfahren zur Darstellung von aromatisch substituirten Amidodinaphtylmethanen.
JPH09504266A (ja) 1993-05-24 1997-04-28 スミスクライン・ビーチャム・コーポレイション 血液調節ペプチド
US6037157A (en) 1995-06-29 2000-03-14 Abbott Laboratories Method for improving pharmacokinetics
US5935982A (en) 1997-02-28 1999-08-10 The University Of North Carolina At Chapel Hill Methods of treating retroviral infection and compounds useful therefor
US6235493B1 (en) 1997-08-06 2001-05-22 The Regents Of The University Of California Amino acid substituted-cresyl violet, synthetic fluorogenic substrates for the analysis of agents in individual in vivo cells or tissue
US6919366B2 (en) 1998-05-22 2005-07-19 Avanir Pharmaceuticals Benzimidazole derivatives as modulators of IgE
US6911462B2 (en) 1998-05-22 2005-06-28 Avanir Pharmaceuticals Benzimidazole compounds for regulating IgE
US6369091B1 (en) 1998-05-22 2002-04-09 Avanir Pharmaceuticals Benzimidazole analogs as down-regulators of IgE
CA2332989A1 (en) 1998-05-22 1999-12-02 Avanir Pharmaceuticals Benzimidazole derivatives as modulators of ige
US6387885B1 (en) 1998-08-26 2002-05-14 Abbott Laboratories 3′,3′-N-bis-desmethyl-3′-N-cycloalkyl erythromycin derivatives as LHRH antagonists
EP2335700A1 (en) 2001-07-25 2011-06-22 Boehringer Ingelheim (Canada) Ltd. Hepatitis C virus polymerase inhibitors with a heterobicylic structure
JP3925265B2 (ja) 2002-03-25 2007-06-06 コニカミノルタホールディングス株式会社 有機エレクトロルミネッセンス素子及びそれを用いた表示装置
TW200304820A (en) 2002-03-25 2003-10-16 Avanir Pharmaceuticals Use of benzimidazole analogs in the treatment of cell proliferation
PL374190A1 (en) 2002-06-14 2005-10-03 Merck & Co, Inc. Mitotic kinesin inhibitors
CA2491895C (en) 2002-07-09 2011-01-18 Vertex Pharmaceuticals Incorporated Inhibitors of c-jun n-terminal kinases (jnk) and other protein kinases
AU2003264038A1 (en) 2002-08-12 2004-02-25 Bristol-Myers Squibb Company Combination pharmaceutical agents as inhibitors of hcv replication
KR100482276B1 (ko) * 2002-08-12 2005-04-13 한국과학기술연구원 피롤계 화합물, 그 중합체 및 이들을 이용한 el 소자
GB0229518D0 (en) 2002-12-19 2003-01-22 Astrazeneca Ab Chemical compounds
US20060003942A1 (en) 2003-10-27 2006-01-05 Roger Tung Combinations for HCV treatment
US20070015757A1 (en) * 2003-12-19 2007-01-18 Novo Nordisk A/S Novel Glucagon Antagonists/Inverse Agonists
BRPI0401908A (pt) 2004-06-04 2006-01-17 Univ Rio De Janeiro Compostos inibidores de serina protease, processo de obtenção e uso para tratamento de flaviviroses
US7772271B2 (en) 2004-07-14 2010-08-10 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US20090208456A1 (en) 2004-07-27 2009-08-20 Gilead Sciences, Inc. Imidazo[4,5-d]pyrimidines, their uses and methods of preparation
BRPI0514316A (pt) 2004-08-13 2008-06-10 Praecis Pharm Inc métodos e composições para modulação de atividade de receptor de esfingosina-1-fosfato (s1p)
TW200633718A (en) * 2004-12-16 2006-10-01 Applied Research Systems Treatment of hepatitis c in the asian population
US7894996B2 (en) 2005-02-28 2011-02-22 The Rockefeller University Structure of the hepatitis C NS5A protein
US8143288B2 (en) 2005-06-06 2012-03-27 Bristol-Myers Squibb Company Inhibitors of HCV replication
PE20070099A1 (es) 2005-06-30 2007-02-06 Janssen Pharmaceutica Nv N-heteroarilpiperazinil ureas como moduladores de la amida hidrolasa del acido graso
WO2007011284A1 (en) 2005-07-15 2007-01-25 Astrazeneca Ab Therapeutic agents
WO2007070556A2 (en) 2005-12-12 2007-06-21 Genelabs Technologies, Inc. N-(6-membered aromatic ring)-amido anti-viral compounds
BRPI0619730A2 (pt) 2005-12-12 2011-10-11 Genelabs Tech Inc compostos antivirais de n-(anel aromático de 5 membros)-amido
ES2378473T3 (es) 2005-12-21 2012-04-12 Abbott Laboratories Compuestos antivirales
US7763731B2 (en) 2005-12-21 2010-07-27 Abbott Laboratories Anti-viral compounds
CA2634699A1 (en) 2005-12-21 2007-06-28 Decode Genetics Ehf N-linked aryl heteroaryl inhibitors of lta4h for treating inflammation
EP1971611B1 (en) 2005-12-21 2012-10-10 Abbott Laboratories Anti-viral compounds
WO2007082554A1 (en) 2006-01-23 2007-07-26 Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa Modulators of hcv replication
MX2008012053A (es) 2006-03-21 2008-12-17 Joyant Pharmaceuticals Inc Promotores de apoptosis de molecula pequeña.
AU2007250443B2 (en) 2006-05-16 2013-06-13 Pharmascience Inc. IAP BIR domain binding compounds
EP2029609A2 (en) 2006-06-08 2009-03-04 Eli Lilly & Company Novel mch receptor antagonists
EP2029530B1 (en) 2006-06-16 2012-09-19 Syngenta Participations AG Ethenyl carboxamide derivatives useful as microbiocides
WO2008014238A2 (en) 2006-07-24 2008-01-31 Tetralogic Pharmaceuticals Corporation Dimeric iap inhibitors
WO2008014236A1 (en) 2006-07-24 2008-01-31 Tetralogic Pharmaceuticals Corporation Dimeric iap inhibitors
US20100158862A1 (en) 2006-08-11 2010-06-24 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
US7659270B2 (en) 2006-08-11 2010-02-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8329159B2 (en) 2006-08-11 2012-12-11 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7745636B2 (en) 2006-08-11 2010-06-29 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8303944B2 (en) 2006-08-11 2012-11-06 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7759495B2 (en) 2006-08-11 2010-07-20 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2008070447A2 (en) 2006-11-21 2008-06-12 Smithkline Beecham Corporation Anti-viral compounds
EP2099778A2 (en) 2006-11-21 2009-09-16 Smithkline Beecham Corporation Amido anti-viral compounds
WO2008074450A2 (en) 2006-12-20 2008-06-26 Nicox S.A. Non-peptidic renin inhibitors nitroderivatives
TWI399380B (zh) 2006-12-20 2013-06-21 Abbott Lab 抗病毒化合物
US8642554B2 (en) 2007-04-12 2014-02-04 Joyant Pharmaceuticals, Inc. Smac mimetic dimers and trimers useful as anti-cancer agents
US7741347B2 (en) 2007-05-17 2010-06-22 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US20090004140A1 (en) 2007-06-26 2009-01-01 Yao-Ling Qiu 4-substituted pyrrolidine as anti-infectives
EP2185154A2 (en) 2007-08-03 2010-05-19 Schering Corporation Method of treating cxcr3 mediated diseases using heterocyclic substituted piperazines
US7728027B2 (en) 2007-08-08 2010-06-01 Bristol-Myers Squibb Company Process for synthesizing compounds useful for treating hepatitis C
US8629171B2 (en) 2007-08-08 2014-01-14 Bristol-Myers Squibb Company Crystalline form of methyl ((1S)-1-((25)-2-(5-(4'-(2-((25)-1((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate dihydrochloride salt
GB0801199D0 (en) 2008-01-23 2008-02-27 Acal Energy Ltd Fuel cells
EP2250160B1 (en) 2008-01-25 2015-11-11 Millennium Pharmaceuticals, Inc. Thiophenes and their use as phosphatidylinositol 3-kinase (pi3k) inhibitors
JP5314053B2 (ja) 2008-02-12 2013-10-16 ブリストル−マイヤーズ スクイブ カンパニー C型肝炎ウイルス阻害剤
KR20100123717A (ko) 2008-02-12 2010-11-24 브리스톨-마이어스 스큅 컴퍼니 C형 간염 바이러스 억제제로서의 헤테로시클릭 유도체
ES2391600T3 (es) 2008-02-13 2012-11-28 Bristol-Myers Squibb Company Imidazoli bifenil imidazoles como inhibidores del virus de la hepatitis C
US7704992B2 (en) 2008-02-13 2010-04-27 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8147818B2 (en) 2008-02-13 2012-04-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2009136290A1 (en) 2008-05-05 2009-11-12 Aegera Therapeutics, Inc. Functionalized pyrrolidines and use thereof as iap inhibitors
WO2009143361A1 (en) 2008-05-22 2009-11-26 Smithkline Beecham Corporation Amido anti-viral compounds
CA2728933A1 (en) 2008-06-27 2009-12-30 Aegera Therapeutics Inc. Bridged secondary amines and use thereof as iap bir domain binding compounds
US7906655B2 (en) 2008-08-07 2011-03-15 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2010015090A1 (en) 2008-08-07 2010-02-11 Aegera Therapeutics Inc. Functionalized pyrrolidines and use thereof as iap inhibitors
US8383094B2 (en) 2008-10-01 2013-02-26 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2010059858A1 (en) 2008-11-19 2010-05-27 Duke University Manassantin compounds and methods of making and using same
JP2010126571A (ja) 2008-11-26 2010-06-10 Toyo Ink Mfg Co Ltd 有機エレクトロルミネッセンス素子材料および有機エレクトロルミネッセンス素子
US8729077B2 (en) 2008-11-28 2014-05-20 Glaxosmithkline Llc Anti-viral compounds, compositions, and methods of use
KR20110098779A (ko) 2008-12-03 2011-09-01 프레시디오 파마슈티칼스, 인코포레이티드 Hcv ns5a의 억제제
EP2373172B1 (en) 2008-12-03 2013-07-17 Presidio Pharmaceuticals, Inc. Inhibitors of hcv ns5a
CN102264737A (zh) 2008-12-23 2011-11-30 雅培制药有限公司 抗病毒化合物
CN102245604A (zh) 2008-12-23 2011-11-16 雅培制药有限公司 抗病毒化合物
US8314135B2 (en) 2009-02-09 2012-11-20 Enanta Pharmaceuticals, Inc. Linked dibenzimidazole antivirals
EP2393359A4 (en) 2009-02-09 2012-10-03 Enanta Pharm Inc COMPOUND DIBENZIMIDAZOLE DERIVATIVES
WO2010096462A1 (en) 2009-02-17 2010-08-26 Enanta Pharmaceuticals, Inc Linked diimidazole derivatives
US8420686B2 (en) 2009-02-17 2013-04-16 Enanta Pharmaceuticals, Inc. Linked diimidazole antivirals
TWI438200B (zh) 2009-02-17 2014-05-21 必治妥美雅史谷比公司 C型肝炎病毒抑制劑
US8637561B2 (en) 2009-02-17 2014-01-28 Enanta Pharmaceuticals, Inc. Linked diimidazole derivatives
US8394968B2 (en) 2009-02-17 2013-03-12 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8242156B2 (en) 2009-02-17 2012-08-14 Enanta Pharmaceuticals, Inc. Linked dibenzimidazole derivatives
US8188132B2 (en) 2009-02-17 2012-05-29 Enanta Pharmaceuticals, Inc. Linked dibenzimidazole derivatives
CA2753313A1 (en) 2009-02-23 2010-08-26 Presidio Pharmaceuticals, Inc. Inhibitors of hcv ns5a
UY32462A (es) 2009-02-23 2010-09-30 Arrow Therapeutics Ltd Derivados de bifenilo novedosos para el tratamiento de infección por virus de hepatitis c 644
US8101643B2 (en) 2009-02-27 2012-01-24 Enanta Pharmaceuticals, Inc. Benzimidazole derivatives
KR101411889B1 (ko) 2009-02-27 2014-06-27 이난타 파마슈티칼스, 인코포레이티드 C형 간염 바이러스 억제제
US8426458B2 (en) 2009-02-27 2013-04-23 Enanta Pharmaceuticals, Inc. Hepatitis C Virus inhibitors
US8507522B2 (en) 2009-03-06 2013-08-13 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
CN102427729B (zh) 2009-03-27 2014-09-03 默沙东公司 丙型肝炎病毒复制的抑制剂
EP2410841A4 (en) 2009-03-27 2012-10-24 Presidio Pharmaceuticals Inc SUBSTITUTED BICYCLIC HCV INHIBITORS
BRPI1012282A2 (pt) 2009-03-27 2015-09-22 Presidio Pharmaceuticals Inc inibidores de anel fundidos da hepatite c.
TWI476190B (zh) 2009-03-30 2015-03-11 必治妥美雅史谷比公司 C型肝炎病毒抑制劑
US8796466B2 (en) 2009-03-30 2014-08-05 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US20110237636A1 (en) 2009-03-30 2011-09-29 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
JP5787876B2 (ja) 2009-04-08 2015-09-30 ビーエーエスエフ ソシエタス・ヨーロピアBasf Se ピロロピロール誘導体、その製造方法及び半導体としての使用
TW201038559A (en) 2009-04-09 2010-11-01 Bristol Myers Squibb Co Hepatitis C virus inhibitors
US8143414B2 (en) 2009-04-13 2012-03-27 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
EP2419404B1 (en) 2009-04-15 2015-11-04 AbbVie Inc. Anti-viral compounds
JP2012524761A (ja) 2009-04-24 2012-10-18 テイボテク・フアーマシユーチカルズ ジアリールエーテル類
US9139569B2 (en) 2009-05-12 2015-09-22 Merck Sharp & Dohme Corp. Fused tricyclic aryl compounds useful for the treatment of viral diseases
TWI689305B (zh) 2009-05-13 2020-04-01 美商基利法瑪席特有限責任公司 抗病毒化合物
US8138215B2 (en) 2009-05-29 2012-03-20 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8211928B2 (en) 2009-05-29 2012-07-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
CA2763140A1 (en) 2009-05-29 2010-12-02 Schering Corporation Antiviral compounds composed of three linked aryl moieties to treat diseases such as hepatitis c
JP2012528194A (ja) 2009-05-29 2012-11-12 メルク・シャープ・アンド・ドーム・コーポレーション C型肝炎などの疾患を処置するための3つの整列型アリール部分で構成された抗菌性化合物
US8937150B2 (en) * 2009-06-11 2015-01-20 Abbvie Inc. Anti-viral compounds
WO2010148006A1 (en) 2009-06-16 2010-12-23 Enanta Pharmaceuticals, Inc. Hepatitis c virus inhibitors
US8221737B2 (en) 2009-06-16 2012-07-17 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US8609648B2 (en) 2009-07-02 2013-12-17 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
WO2011004276A1 (en) 2009-07-06 2011-01-13 Pfizer Limited Hepatitis c virus inhibitors
US8354419B2 (en) 2009-07-16 2013-01-15 Vertex Pharmaceuticals Incorporated Benzimidazole analogues for the treatment or prevention of flavivirus infections
EP2462135A1 (en) 2009-08-07 2012-06-13 Janssen R&D Ireland Bis-benzimidazole derivatives as hepatitis c virus inhibitors
US20120172368A1 (en) 2009-09-03 2012-07-05 Koen Vandyck Bis-Benzimidazole Derivatives
EP2473056A4 (en) 2009-09-04 2013-02-13 Glaxosmithkline Llc CHEMICAL COMPOUNDS
US8703938B2 (en) 2009-09-11 2014-04-22 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US8822700B2 (en) 2009-09-11 2014-09-02 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US8927709B2 (en) 2009-09-11 2015-01-06 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
WO2011031934A1 (en) 2009-09-11 2011-03-17 Enanta Pharmaceuticals, Inc. Hepatitis c virus inhibitors
US8759332B2 (en) 2009-09-11 2014-06-24 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
EP2475256A4 (en) 2009-09-11 2013-06-05 Enanta Pharm Inc HEPATITIS C-VIRUS HEMMER
US8815928B2 (en) 2009-09-11 2014-08-26 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
WO2011050146A1 (en) 2009-10-23 2011-04-28 Glaxosmithkline Llc Chemical compounds
UA108211C2 (uk) 2009-11-04 2015-04-10 Янссен Рід Айрленд Бензімідазолімідазольні похідні
US20110274648A1 (en) 2009-11-11 2011-11-10 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
US20110269956A1 (en) 2009-11-11 2011-11-03 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
US20110281910A1 (en) 2009-11-12 2011-11-17 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
EP2503881B1 (en) 2009-11-25 2015-05-13 Merck Sharp & Dohme Corp. Fused tricyclic compounds and derivatives thereof useful for the treatment of viral diseases
MY179840A (en) 2009-12-04 2020-11-18 National Health Res Inst Proline derivatives
US8653070B2 (en) 2009-12-14 2014-02-18 Enanta Pharmaceuticals, Inc. Hepatitis C virus inhibitors
US8377980B2 (en) 2009-12-16 2013-02-19 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
CA2784748A1 (en) 2009-12-18 2011-06-23 Idenix Pharmaceuticals, Inc. 5,5-fused arylene or heteroarylene hepatitis c virus inhibitors
CN104530079B (zh) 2009-12-18 2017-10-20 北京凯因科技股份有限公司 C型肝炎病毒复制的新型抑制剂
CA2785488A1 (en) 2009-12-22 2011-07-21 Merck Sharp & Dohme Corp. Fused tricyclic compounds and methods of use thereof for the treatment of viral diseases
MX2012007420A (es) 2009-12-24 2012-07-23 Vertex Pharma Analogos para el tratamiento o prevencion de infecciones de flavivirus.
US8362020B2 (en) 2009-12-30 2013-01-29 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2011091446A1 (en) 2010-01-22 2011-07-28 Glaxosmithkline Llc Chemical compounds
BR112012018529A2 (pt) 2010-01-25 2016-08-09 Enanta Pharm Inc inibidores do vírus de hepatite c, sua composição farmacêutica e seu uso, e método para inibição da replicação de um vírus contendo rna
WO2011091532A1 (en) 2010-01-28 2011-08-04 Boehringer Ingelheim International Gmbh Hepatitis c inhibitor compounds
US8178531B2 (en) 2010-02-23 2012-05-15 Enanta Pharmaceuticals, Inc. Antiviral agents
MX2012010252A (es) 2010-03-04 2013-02-01 Enanta Pharm Inc Agentes farmaceuticos en combinacion como inhibidores de la replicacion del virus de hepatitis c (hcv).
AU2011224698A1 (en) 2010-03-09 2012-11-01 Merck Sharp & Dohme Corp. Fused Tricyclic Silyl Compounds and methods of use thereof for the treatment of viral diseases
TW201141857A (en) 2010-03-24 2011-12-01 Vertex Pharma Analogues for the treatment or prevention of flavivirus infections
EP2550262A1 (en) 2010-03-24 2013-01-30 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
EP2550267A1 (en) 2010-03-24 2013-01-30 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
JP2013522377A (ja) 2010-03-24 2013-06-13 バーテックス ファーマシューティカルズ インコーポレイテッド フラビウイルス感染を処置または予防するためのアナログ
EP2555622A4 (en) 2010-04-09 2013-09-18 Enanta Pharm Inc HEPATITIS C-VIRUS HEMMER
US20110312996A1 (en) 2010-05-17 2011-12-22 Intermune, Inc. Novel inhibitors of hepatitis c virus replication
CA2800530A1 (en) 2010-05-28 2011-12-01 Presidio Pharmaceuticals, Inc. Inhibitors of hcv ns5a
EP2575819A4 (en) 2010-06-04 2013-11-27 Enanta Pharm Inc INHIBITORS OF HEPATITIS C VIRUS
EP2580209A4 (en) 2010-06-09 2013-11-06 Presidio Pharmaceuticals Inc INHIBITORS OF HCV NS5A PROTEIN

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5095153A (en) 1988-09-30 1992-03-10 Himont Incorporated Diethers usable in the preparation of ziegler-natta catalysts
US20090076076A1 (en) 2007-06-13 2009-03-19 Baylor University Inhibitors of cysteine proteases and methods of use thereof
WO2010144646A2 (en) * 2009-06-11 2010-12-16 Abbott Laboratories Anti-viral compounds
US20100317568A1 (en) 2009-06-11 2010-12-16 Abbott Labaoratories Anti-Viral Compounds
US20110092415A1 (en) 2009-06-11 2011-04-21 Abbott Labaoratories Anti-Viral Compounds
US20110207699A1 (en) 2009-06-11 2011-08-25 Abbott Labaoratories Anti-Viral Compounds

Non-Patent Citations (23)

* Cited by examiner, † Cited by third party
Title
ALDOUS ET AL., TETRAHEDRON: ASYMMETRY, vol. 11, 2000, pages 2455 - 2462
BIOORG. MED. CHEM. LETT., 2009, pages 5684,5686
BUNGARD, H.: "DESIGN OF PRODRUGS", 1985, ELSEVIER, pages: 7 - 24
CHARIFSON, P.S. ET AL., J. MED. CHEM., vol. 51, 2008, pages 5243 - 5263
CHONG ET AL., TETRAHEDRON: ASYMMETRY, vol. 6, 1995, pages 409 - 418
GREENE; WUTS: "PROTECTING GROUPS IN CHEMICAL SYNTHESIS", 1999, JOHN WILEY & SONS
J. AM. CHEM. SOC, vol. 73, 1951, pages 5171
J. AM. CHEM. SOC., 1965, pages 1353,1358
J. ORG. CHEM., 1972, pages 4075,4076,4077
JING ET AL., ADV. SYNTH. CATAL., vol. 347, 2005, pages 1193 - 1197
LI ET AL., TETRAHEDRON, vol. 63, 2007, pages 8046 - 8053
MASUI ET AL., SYNLETT, 1997, pages 273 - 274
MEYER ET AL., SYNLETT, 2003, pages 1427 - 1430
MEYER ET AL., SYNTHESIS, 2005, pages 945 - 956
NEVAR ET AL., SYNTHESIS, 2000, pages 1259 - 1262
PATEL ET AL., J MEDICINAL CHEMISTRY, vol. 49, no. 25, 2006, pages 7450
PENNING ET AL., BIOORG. MED. CHEM., vol. 16, 2008, pages 6965 - 6975
SATO ET AL., SYNTHESIS, 2004, pages 1434 - 1438
SYNLETT, 2003, pages 1427 - 1430
SYNTHESIS, 2003, pages 2507 - 2510
SYNTHESIS, 2005, pages 945 - 956
TET. LETT., 2003, pages 5807 - 5810
TETRAHEDRON, 2003, pages 2701 - 2712

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020059696A (ja) * 2010-10-13 2020-04-16 アッヴィ・アイルランド・アンリミテッド・カンパニー 抗ウィルス化合物
US9340520B2 (en) 2011-02-07 2016-05-17 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9546160B2 (en) 2011-05-12 2017-01-17 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US10201541B1 (en) 2011-05-17 2019-02-12 Abbvie Inc. Compositions and methods for treating HCV
US10201584B1 (en) 2011-05-17 2019-02-12 Abbvie Inc. Compositions and methods for treating HCV
US9326973B2 (en) 2012-01-13 2016-05-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
JP2015528511A (ja) * 2012-09-18 2015-09-28 アッヴィ・インコーポレイテッド C型肝炎を治療するための方法
JP2021054849A (ja) * 2012-09-18 2021-04-08 アッヴィ・インコーポレイテッド C型肝炎を治療するための方法
JP2018109035A (ja) * 2012-09-18 2018-07-12 アッヴィ・インコーポレイテッド C型肝炎を治療するための方法
JP2019194241A (ja) * 2012-09-18 2019-11-07 アッヴィ・インコーポレイテッド C型肝炎を治療するための方法
JP2016513695A (ja) * 2013-03-14 2016-05-16 アッヴィ・インコーポレイテッド C型肝炎を治療するための2種の抗ウイルス剤の併用
US11484534B2 (en) 2013-03-14 2022-11-01 Abbvie Inc. Methods for treating HCV
JP2021130720A (ja) * 2013-03-14 2021-09-09 アッヴィ・インコーポレイテッド C型肝炎を治療するための2種の抗ウイルス剤の併用
JP2020037589A (ja) * 2013-03-14 2020-03-12 アッヴィ・インコーポレイテッド C型肝炎を治療するための2種の抗ウイルス剤の併用
JP2019048868A (ja) * 2013-03-14 2019-03-28 アッヴィ・インコーポレイテッド C型肝炎を治療するための2種の抗ウイルス剤の併用
US10286029B2 (en) 2013-03-14 2019-05-14 Abbvie Inc. Method for treating HCV
US9717712B2 (en) 2013-07-02 2017-08-01 Bristol-Myers Squibb Company Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis C virus
US9770439B2 (en) 2013-07-02 2017-09-26 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9775831B2 (en) 2013-07-17 2017-10-03 Bristol-Myers Squibb Company Combinations comprising biphenyl derivatives for use in the treatment of HCV
US10105365B2 (en) 2014-01-03 2018-10-23 Abbvie Inc. Solid antiviral dosage forms
US9744170B2 (en) 2014-01-03 2017-08-29 Abbvie Inc. Solid antiviral dosage forms
US9333204B2 (en) 2014-01-03 2016-05-10 Abbvie Inc. Solid antiviral dosage forms
US10617675B2 (en) 2015-08-06 2020-04-14 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US10730874B2 (en) 2018-03-13 2020-08-04 Shire Human Genetic Therapies, Inc. Inhibitors of plasma kallikrein and uses thereof
US11352356B2 (en) 2018-03-13 2022-06-07 Takeda Pharmaceutical Company Limited Inhibitors of plasma kallikrein and uses thereof
US11370803B2 (en) 2019-09-18 2022-06-28 Takeda Pharmaceutical Company Limited Heteroaryl plasma kallikrein inhibitors
US11787796B2 (en) 2019-09-18 2023-10-17 Takeda Pharmaceutical Company Limited Plasma Kallikrein inhibitors and uses thereof

Also Published As

Publication number Publication date
JP2014510063A (ja) 2014-04-24
US20120172290A1 (en) 2012-07-05
HUS1700040I1 (hu) 2017-11-28
MX346264B (es) 2017-03-13
US20120220562A1 (en) 2012-08-30
MX2013009763A (es) 2014-01-31
TW201247648A (en) 2012-12-01
CN103596941B (zh) 2015-07-08
EP2678334A1 (en) 2014-01-01
US9394279B2 (en) 2016-07-19
ES2624246T3 (es) 2017-07-13
CN103596941A (zh) 2014-02-19
EP2678334B1 (en) 2017-03-22
CA2828495A1 (en) 2012-08-30
TWI586660B (zh) 2017-06-11

Similar Documents

Publication Publication Date Title
US10028937B2 (en) Anti-viral compounds
US8921514B2 (en) Anti-viral compounds
EP2678334B1 (en) Anti-viral compounds
JP6790202B2 (ja) 抗ウィルス化合物
AU2016238925B2 (en) Anti-viral compounds
AU2014203655B2 (en) Anti-viral compounds
US20230285378A1 (en) Anti-Viral Compounds

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12716757

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2828495

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2013555589

Country of ref document: JP

Kind code of ref document: A

REEP Request for entry into the european phase

Ref document number: 2012716757

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: MX/A/2013/009763

Country of ref document: MX

Ref document number: 2012716757

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE